In Supportive Care Oncology

Transcription

1 C A N A D I A N V I S I O N F O R R H E U M A T O L O G Y In Supportive Care Oncology Number 11 March 2014 Looking Ahead PUBLICATIONS MAIL AGREEMENT NO RETURN UNDELIVERABLE CANADIAN ADDRESSES TO Preventing Long-term Comorbidities NEW EVIDENCE 219 DUFFERIN ST. (SOUTH BUILDING, SUITE 215C) TORONTO ON M6K 3J1 I N S I D E New Evidence in Rheumatology is an independent medical news reporting service providing educational updates on current medical events. Views expressed are those of the participants and do not necessarily reflect those of the publisher or the sponsor. Support for development and distribution of this report was provided by Hoffmann-La Roche Rheumatology. Any therapies mentioned in this report should be used in accordance with the recognized prescribing information. No claims or endorsements are made for any products, uses, or doses presently under investigation. Information provided herein is not intended to serve as the sole basis for individual care. Our objective is to facilitate understanding of current trends in rheumatology for physicians and allied healthcare providers. T H I S I S S U E RITUXIMAB IN RA TREATMENT Novel Treatment Strategies for Rituximab: Safety and Efficacy Studies TOCILIZUMAB IN RA TREATMENT COMORBIDITIES IN RA The Effect of Tocilizumab Treatment on RA and Associated Comorbidities The Impact of RA Disease Activity on Associated Comorbidities Interviews with Dr. Gerd Burmester and Dr. Katerina Chatzidionysiou

2 In Supportive Care Oncology Publisher Paul Borlinha Managing Director Anna Christofides, MSc, RD Medical Writers Ghada Kurban, PhD Cassandra Uchida, PhD Editor Ben Fuerth, MSc Creative Director Jobet Dimaculangan Art Director Andrew Oyen Website Design Ronaji Naranjo Website Development Xinyu Pu New Evidence in Rheumatology is published by New Evidence 219 Dufferin St. (South Building, Suite 215C) Toronto, Ontario M6K 3J1 Correspondence should be addressed to: New Evidence 219 Dufferin St. (South Building, Suite 215C) Toronto, Ontario M6K 3J1 fax: website: To join our mailing list or to request back issues, please contact us by mail, fax: , or New Evidence in Rheumatology is also available online at Canada Post Canadian Publications Mail Product Sales Agreement Number New Evidence in Rheumatology is a publication for Canadian rheumatology healthcare professionals. Our journal provides rheumatology specialists with scientific data from research presented at international and Canadian rheumatology conferences. A special feature of the journal, the Canadian Perspective, gives key opinion leaders a forum to discuss recent developments in rheumatology and to comment on how these advances may shape Canadian clinical practice. In addition, the Investigator Commentary sections provide information on key clinical studies from interviews with principal investigators. New Evidence also publishes discussion and expert opinion papers on timely topics of interest to rheumatologists in Canada. Our March 2014 issue summarizes and discusses the latest research in rheumatoid arthritis (RA). Key studies on novel RA treatment strategies are included, focusing on the rapid infusion delivery method for rituximab, retreatment strategies for rituximab, and the subcutaneous formulation of tocilizumab. In addition, the effects of RA disease activity on various RA comorbidities are investigated, including cardiovascular disease, liver dysfunction, chronic kidney disease, interstitial lung disease, and cancer. We would like to thank Dr. Janet Pope for her Canadian Perspectives, as well as Dr. Gerd Burmester and Dr. Katerina Chatzidionysiou for their Investigator Commentaries. We invite you to visit our website at for the online version of New Evidence and more reports on current research. Slide presentations on various topics are available for download. Cert no. SW-COC New Evidence in Rheumatology March

3 Contents Tocilizumab in Rheumatoid Arthritis Treatment In Supportive Care Oncology Tocilizumab in Rheumatoid Arthritis Treatment 6 Tocilizumab is Effective and Safe for the Treatment of Rheumatoid Arthritis, with no Adverse Effects on Associated Comorbidities The SUMMACTA study: efficacy and safety of tocilizumab subcutaneous versus tocilizumab intravenous, in combination with traditional DMARDs, in patients with rheumatoid arthritis at 49 weeks. (Burmester GR, et al. ACR 2013:464) The BREVACTA study: efficacy and safety of tocilizumab subcutaneous in combination with traditional DMARDs for up to 48 weeks in patients with moderate-to-severe rheumatoid arthritis. (Kivitz A, et al. ACR 2013:1428) Tocilizumab monotherapy compared with adalimumab monotherapy in patients with rheumatoid arthritis: an evaluation of high-density lipoprotein composition. (Gabay C, et al. ACR 2013:450) Transaminase levels and hepatic events observed during tocilizumab treatment: pooled analysis of long-term clinical trial safety data in patients with rheumatoid arthritis. (Genovese MC, et al. ACR 2013:459) Comparative efficacy of novel DMARDs as monotherapy and Investigator Commentary 34 in combination with methotrexate in rheumatoid arthritis patients with an inadequate response to traditional DMARDs: a network meta-analysis. (Buckley F, et al. ACR 2013:460) Tocilizumab in combination therapy and monotherapy versus methotrexate in methotrexate-naïve patients with early rheumatoid arthritis: clinical and radiographic outcomes from a randomized, placebo-controlled trial. (Burmester GR, et al. ACR 2013:2767) Tocilizumab in patients with rheumatoid arthritis and rates of malignancy: results from clinical trials. (van Vollenhoven RF, et al. ACR 2013:2351) Canadian Perspective by Dr. Janet Pope An Interview with Dr. Gerd Burmester on the SUMMACTA Trial, Comparing Two Methods of Tocilizumab Delivery 2 New Evidence in Rheumatology March 2014

4 Tocilizumab in Rheumatoid Arthritis Treatment In Supportive Care Oncology Rituximab in Rheumatoid Arthritis Treatment 36 Rituximab: Long-term Safety, Efficacy, and Treatment Strategies Long-term safety of rituximab: pooled analysis of the rheumatoid arthritis global clinical trial program over 11 years. (van Vollenhoven RF, et al. ACR 2013:2342) Use of rituximab as a second-line biologic agent compared with adalimumab, etanercept, and infliximab in patients with rheumatoid arthritis a report from the RHUMADATA clinical database and registry. (Bessette L, et al. ACR 2013:432) Results from the RATE-RA study: a multicentre, single-arm study to evaluate the safety of administering rituximab at a more rapid infusion rate in patients with rheumatoid arthritis. (Pritchard CH, et al. ACR 2013:877) Fixed versus on-flare retreatment with rituximab in RA results from the CERERRA collaboration. (Chatzidionysiou K, et al. ACR 2013:500) Effectiveness of repeated courses of rituximab in RA results from the CERERRA collaboration. (Chatzidionysiou K, et al. ACR 2013:496) Canadian Perspective by Dr. Janet Pope Comorbidities in Rheumatoid Arthritis 56 Rheumatoid Arthritis Disease Activity Correlates with Increased Cardiovascular Disease, Chronic Kidney Disease, and Interstitial Lung Disease Cardiovascular diseases in rheumatoid arthritis: can early treatment with disease-modifying antirheumatic drugs alter the risk? (Desai R, et al. ACR 2013:833) Outcomes of patients with rheumatoid arthritis and comorbid hyperlipidemia. (Rosenblatt L, et al. ACR 2013:356) Inflammatory burden predicts carotid plaque progression and subsequent cardiovascular events in rheumatoid arthritis: the two-year prospective KARRA study. (Im CH, et al. ACR 2013:358) Tocilizumab treatment increases left ventricular ejection fraction and decreases left ventricular mass index in rheumatoid arthritis patients without cardiac symptoms: assessment by cardiac magnetic resonance imaging at 3.0 Tesla. (Hitomi K, et al. ACR 2013:359) Active rheumatoid arthritis is an independent risk factor for chronic kidney disease. (Hanaoka R, et al. ACR 2013:380) Rheumatoid arthritis-associated interstitial lung disease: lung inflammation evaluated with high resolution computed tomography scan is correlated to rheumatoid arthritis disease activity. (Rojas-Serrano J, et al. ACR 2013:409) Investigator Commentary 53 An Interview with Dr. Katerina Chatzidionysiou on the Use of Rituximab in the Treatment of Rheumatoid Arthritis New Evidence in Rheumatology March

5 Contributors Canadian Perspectives Janet Pope, MD, MPH, FRCPC Dr. Janet Pope is a Professor of Medicine at Western University, London, Ontario, Canada. She is a rheumatologist and epidemiologist and is the Division Head in Rheumatology at St. Joseph s Hospital, London, Ontario. She has a major interest in scleroderma research, including membership in the Canadian Scleroderma Research Group (CSRG) and the Scleroderma Clinical Trials Consortium (SCTC). Dr. Pope is co-leading the new ACR/EULAR guidelines for systemic sclerosis and has published over 250 peer-reviewed articles. In 2013, she was the recipient of the Canadian Rheumatology Association s Distinguished Investigator Award and was named Rheumatologist of the Year by the Ontario Rheumatology Association. She supervises students at all levels and runs two nation-wide studentships for the purposes of exposing medical students to clinical rheumatology or research in rheumatology. 4 New Evidence in Rheumatology March 2014

6 Investigator Commentaries Gerd R. Burmester, MD Dr. Gerd R. Burmester is a Professor of Medicine in the Department of Rheumatology and Clinical Immunology at the Charité University Hospital, Free University and Humboldt University of Berlin, Germany. Dr. Burmester earned his medical degree from Hannover Medical School and completed a residency at the Medical School of the University of Erlangen-Nuremberg. He was awarded a postdoctoral fellowship at Rockefeller University in New York, and was a visiting scholar at the Hospital for Joint Diseases, Mount Sinai School of Medicine, New York. Dr. Burmester is the recipient of numerous awards, including the Jan van Breemen Medal of the Dutch Society of Rheumatology and the Carol-Nachman Prize for Rheumatology. He serves on several editorial boards, including the Journal of Rheumatology and Clinical Rheumatology, and he is the Associate Editor of Annals of the Rheumatic Diseases. Dr. Burmester served as President of the German Society of Rheumatology from 2001 to He was a member of the Executive Committee of the European League Against Rheumatism (EULAR) from 2003 to 2006, acting as Chairman of the Standing Committee on Investigative Rheumatology and became an honorary member of EULAR in From 2011 to 2013, he served as Treasurer of EULAR, and he was elected President Elect of EULAR in Katerina Chatzidionysiou, MD Dr. Katerina Chatzidionysiou received her medical degree in 2007 from the Aristotle University of Thessaloniki, Greece. Since 2008, she has been a resident physician and research fellow in the Rheumatology Department at the Karolinska University Hospital and in the Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID) at Karolinska Institute in Stockholm, Sweden. She has assumed the role of clinical sub-investigator for numerous clinical trials of biologic treatments in rheumatoid arthritis and systemic lupus erythematosus. Her research interests focus on registry-based epidemiological studies of biologic treatments, mainly tumour necrosis factor inhibitors and rituximab, in rheumatoid arthritis. New Evidence in Rheumatology March

7 Tocilizumab in Rheumatoid Arthritis Treatment Tocilizumab is Effective and Safe for the Treatment of Rheumatoid Arthritis, with no Adverse Effects on Associated Comorbidities The interleukin-6 receptor inhibitor tocilizumab is known to be an efficacious treatment for rheumatoid arthritis (RA). 1,2 The safety of tocilizumab has been demonstrated in phase III trials, and long-term safety data are continuing to be reported. 3,4 While the overall safety of tocilizumab is becoming more established, little is known about the effect tocilizumab may have on the development or progression of comorbidities associated with RA and/ or the long-term use of biologics, including hepatic dysfunction, cardiovascular disease, and cancer. At the 2013 American College of Rheumatology (ACR) Annual Meeting, investigators presented data on the safety and efficacy of the subcutaneous (sc) and intravenous (iv) formulations of tocilizumab (both in monotherapy and in combination with diseasemodifying antirheumatic drugs [DMARDs]), an evaluation of the ability of tocilizumab and adalimumab to reduce dyslipidemia, the effects of tocilizumab on hepatic function, and meta-analyses comparing the efficacy of novel DMARDs and evaluating the rates of malignancy in patients with RA who were treated with tocilizumab. This article reports on seven presentations that were delivered at ACR 2013: A long-term analysis of the SUMMACTA study, comparing the efficacy and safety of tocilizumab sc and iv in monotherapy, confirmed that the efficacy and safety profiles of tocilizumab sc remained comparable to those of tocilizumab iv after 49 weeks of treatment. A report on the BREVACTA study, which examined the safety and efficacy of tocilizumab sc in combination with DMARDs, demonstrated sustained ACR response and reduced progression of joint damage over 48 weeks of treatment with the tocilizumab sc combination regimen when compared with placebo, with a similar safety profile to that of tocilizumab iv. A subanalysis of the ADACTA trial, which compared tocilizumab and adalimumab in monotherapy, showed that tocilizumab, to a greater extent than adalimumab, changed high-density lipoprotein composition towards a more atheroprotective phenotype. A pooled analysis of multiple trials investigated the effects of tocilizumab treatment on hepatic function, and found that while mean transaminase levels increased early in tocilizumab treatment, these elevations were managed with dose reductions or interruptions. Additionally, most severe elevations were single occurrences, and the rate of hepatic serious adverse events was similar to that of the general population of patients with RA. A meta-analysis compared novel DMARDs, both in monotherapy and in combination with methotrexate, and demonstrated that tocilizumab monotherapy is associated with a greater ACR response than those observed with tumour necrosis factor inhibitors or tofacitinib. Additionally, the response to tocilizumab monotherapy was similar to that of tocilizumab and methotrexate in combination therapy. The FUNCTION study compared radiographic outcomes in patients treated with methotrexate with or without tocilizumab, and found that patients treated with tocilizumab achieved greater inhibition of structural joint damage than with methotrexate alone. An analysis of multiple clinical trials assessed the risk for malignancy in patients with RA who were exposed to long-term tocilizumab therapy, and found that the overall risk for malignancy was not statistically different from that in the U.S. general population. References: 1. Oldfield V, Dhillon S, Plosker GL. Tocilizumab: a review of its use in the management of rheumatoid arthritis. Drugs 2009;69: Hoffmann-La Roche Ltd. Pr ACTEMRA (tocilizumab) Product Monograph. May 31, Nishimoto N, Miyasaka N, Yamamoto K, et al. Long-term safety and efficacy of tocilizumab, an anti-il-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study. Ann Rheum Dis 2009;68: Schiff MH, Kremer JM, Jahreis A, et al. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther 2011;13:R New Evidence in Rheumatology March 2014

8 In Supportive Care Oncology Burmester GR, et al. ACR 2013:464 The SUMMACTA study: efficacy and safety of tocilizumab subcutaneous versus tocilizumab intravenous, in combination with traditional DMARDs, in patients with rheumatoid arthritis at 49 weeks Background Tocilizumab is a recombinant humanized monoclonal antibody directed against the interleukin-6 receptor. Intravenous (iv) tocilizumab in combination with disease-modifying antirheumatic drugs (DMARDs) has demonstrated efficacy with a manageable safety profile in patients with rheumatoid arthritis (RA) who had an inadequate response to DMARDs or tumour necrosis factor inhibitors (TNF-Is). The SUMMACTA study demonstrated the efficacy and safety of subcutaneous (sc) tocilizumab in combination with DMARDs. Patients with RA in this trial were re-randomized to receive either tocilizumab sc or tocilizumab iv in the openlabel period; the cumulative safety, immunogenicity, and efficacy were evaluated at 49 weeks. 1 Study design Patients with RA were randomized 1:1 to receive tocilizumab sc 162 mg weekly (qw) and placebo iv every four weeks (q4w), or tocilizumab iv 8 mg/kg q4w and placebo sc qw. During the study, patients remained on a background stable dose of at least one nonbiologic DMARD. At week 24, all patients were re-randomized for an open-label extension: Patients who received tocilizumab sc were re-randomized 11:1 to receive tocilizumab sc qw or tocilizumab iv q4w; Patients who received tocilizumab iv were rerandomized 2:1 to receive tocilizumab iv q4w or tocilizumab sc qw. Endpoints at week 49 for the open-label extension included the proportions of patients who: Had American College of Rheumatology (ACR) 50 and ACR70 responses; Had a 28-joint disease activity score (DAS28) <2.6; Had a decrease of 0.3 from baseline in the health assessment questionnaire-disability index (HAQ-DI); Withdrew due to lack of therapeutic response. Key findings Baseline characteristics and disposition Baseline demographics and clinical characteristics of the patients were balanced across groups, including (sc/ iv): Female: 82.4%/82.6%; Mean age: 52.7/52.8 years; Mean duration of RA: 8.7/8.6 years; Mean DAS28: 6.6/6.7; Mean HAQ-DI: 1.6/1.7; Patients receiving corticosteroids at baseline: 54.5%/53.6%; Patients who did not respond to TNF-Is: 22.5%/21.6%. Study design Screening R TCZ-sc 162 mg qw + placebo-iv q4w TCZ-iv 8 mg/kg q4w + placebo-sc qw R R TCZ-sc qw TCZ-iv q4w TCZ-sc qw TCZ-iv q4w 72-week OLE 24-week double-blind period Baseline week 24 week 49 week 105 iv = intravenous; OLE = open-label extension; qw = weekly; q4w = every four weeks; R = randomization; sc = subcutaneous; TCZ = tocilizumab New Evidence in Rheumatology March

9 Of the 573 patients who completed the double-blind period on tocilizumab sc, 521 patients continued on tocilizumab sc during the open-label extension and 48 patients switched to tocilizumab iv. Of the 564 patients who completed the double-blind period on tocilizumab iv, 372 patients continued on tocilizumab iv during the open-label extension and 186 patients switched to tocilizumab sc. From week 24 to 49, eight (2%) patients in the tocilizumab sc group and 11 (3%) patients in the tocilizumab-iv group withdrew due to insufficient therapeutic response. From week 24 to 49, one (<1%) patient who switched from tocilizumab iv to sc and one (2%) patient who switched from tocilizumab sc to iv withdrew due to insufficient therapeutic response. Efficacy A similar proportion of patients in the tocilizumab sc and iv arms achieved ACR20/50/70 responses, DAS28 remission, and a decrease of 0.3 in HAQ-DI score over 49 weeks. (Figures 1, 2, and 3) Efficacy in patients after switching from tocilizumab iv to sc and vice versa was comparable to that in patients who received continuous tocilizumab sc or iv. (Figures 1, 2, and 3) Figure 1. Patients who achieved ACR20/50/70 responses 80 TCZ-sc qw (N = 631) TCZ-iv q4w (N = 631) 76.2 Patients who achieved an ACR response (%) ACR20 ACR50 ACR ACR20, % ACR50, % ACR70, % TCZ-iv to TCZ-sc (N = 186) Week TCZ-sc to TCZ-iv (N = 48) Week Week ACR = American College of Rheumatology; iv = intravenous; qw = weekly; q4w = every four weeks; sc = subcutaneous; TCZ = tocilizumab Figure 2. Patients who achieved DAS28 < TCZ-sc qw (N = 631) TCZ-iv q4w (N = 631) Patients who achieved DAS28 <2.6 (%) TCZ-iv to TCZ-sc (N = 186) Week 49 TCZ-sc to TCZ-iv (N = 48) Week 49 DAS28 <2.6, % Week 24 Week 49 DAS28 = 28-joint disease activity score; iv = intravenous; qw = weekly; q4w = every four weeks; sc = subcutaneous; TCZ = tocilizumab 8 New Evidence in Rheumatology March 2014

10 In Supportive Care Oncology Figure 3. Patients who achieved a decrease of 0.3 in HAQ-DI 100 TCZ-sc qw (N = 631) TCZ-iv q4w (N = 631) Patients who achieved a decrease of 0.3 in HAQ-DI (%) ΔHAQ-DI from baseline 0.3, % TCZ-iv to TCZ-sc (N = 186) Week 49 TCZ-sc to TCZ-iv (N = 48) Week Week 24 Week 49 HAQ-DI = health assessment questionnaire-disability index; iv = intravenous; qw = weekly; q4w = every four weeks; sc = subcutaneous; TCZ = tocilizumab Safety The safety profile of tocilizumab sc remained stable over time and was comparable to that of tocilizumab iv. From week 24 to 49, three deaths occurred in the tocilizumab sc group (thrombosis, shock, and unknown cause) and three deaths occurred in the tocilizumab-iv group (idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and ischemic infarction of the right occipital lobe). The safety profile of switching from tocilizumab iv to sc and vice versa was similar to that of continuous treatment. Two deaths were reported in the iv-to-sc arm (pneumonia and sepsis), and no deaths occurred in the sc-to-iv arm. Injection-site reactions (ISRs) occurred more frequently in the tocilizumab-sc group than in the tocilizumab-iv group (treated with placebo sc), but the overall ISR frequency decreased over time. (Table 1) All ISRs were nonserious and grade 1 or 2. In the tocilizumab-sc group, a total of 10.0% and 12.0% of patients had ISRs at weeks 24 and 49, respectively; 6.5% of patients in the tocilizumab-iv-to-sc group had ISRs at week 49. In the tocilizumab-iv group, a total of 2.4% of patients had ISRs at weeks 24 and 49; 0% of patients in the tocilizumab-sc-to-iv group had ISRs at week 49. From week 24 to 49, there was one patient in the tocilizumab sc arm who withdrew due to an injection-site erythema adverse event, and the event resolved with no sequelae. Table 1. Injection-site reactions (safety population) TCZ-sc 162 mg qw TCZ-iv 8 mg/kg q4w TCZ-iv to TCZ-sc TCZ-sc to TCZ-iv Week 24 Week 49 Week 24 Week 49 Week 49 Week 49 N Patients with ISRs, n (%) 64 (10.0) 76 (12.0) 15 (2.4) 15 (2.4) 12 (6.5) 0 (0.0) Total ISRs symptoms, no (0.0) Erythema, n (%) 28 (4.4) 35 (5.5) 5 (0.8) 5 (0.8) 9 (4.8) 0 (0.0) Pain, n (%) 12 (1.9) 15 (2.4) 5 (0.8) 5 (0.8) 2 (1.1) 0 (0.0) Pruritus, n (%) 14 (2.2) 17 (2.7) 0 (0.0) 0 (0.0) 2 (1.1) 0 (0.0) Hematoma, n (%) 5 (0.8) 9 (1.4) 5 (0.8) 5 (0.8) 0 (0.0) 0 (0.0) ISRs that led to withdrawal, n (%) 0 (0.0) 1 (0.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) iv = intravenous; ISRs = injection-site reactions; qw = weekly; q4w = every four weeks; sc = subcutaneous; TCZ = tocilizumab New Evidence in Rheumatology March

11 There was no association between grade 3 or 4 neutropenia and serious infections, and there was no association between grade 3 or 4 thrombocytopenia and serious bleeding events. From week 24 to 49, a similar frequency of elevated liver enzymes was observed for all treatment groups; there were no reports of clinical Hy s Law cases. The mean tocilizumab concentrations during the open-label extension in patients who switched from tocilizumab iv to sc and vice versa at week 25 were comparable to concentrations in patients who received tocilizumab sc or iv throughout the study. (Figure 4) The number of patients who developed anti-tocilizumab antibodies was similar between all groups. (Table 2) None of the patients who developed anti-tocilizumab antibodies developed serious or clinically significant hypersensitivity, or experienced loss of efficacy. Table 2. Immunogenicity at week 49 (safety population) n (%) Patients tested by screening assay at any time point Confirmation assay positive* Neutralization assay positive* TCZ-sc 162 mg qw (N = 631) TCZ-iv 8 mg/kg q4w (N = 631) TCZ-iv to TCZ-sc (N = 186) TCZ-sc to TCZ-iv (N = 48) 629 (99.7) 630 (99.8) 186 (100) 48 (100) 8 (1.3) 7 (1.1) 2 (1.1) 1 (2.1) 8 (1.3) 7 (1.1) 2 (1.1) 1 (2.1) IgE assay positive 2 (0.3) IgE = immunoglobulin E; iv = intravenous; qw = weekly; q4w = every four weeks; sc = subcutaneous; TCZ = tocilizumab *Patients were seronegative at baseline. Figure 4. Tocilizumab serum concentration (predose) over time Serum TCZ concentration (µg/ml) TCZ-sc qw (N = 521) TCZ-iv q4w (N = 372) TCZ-iv to TCZ-sc (N = 186) TCZ-sc to TCZ-iv (N = 48) BL Time since first dose (weeks)* 85 BL = baseline; iv = intravenous; qw = weekly; q4w = every four weeks; sc = subcutaneous; TCZ = tocilizumab *There was a 1-week dose interruption period (week 24-25) before the first dosing in the open-label period at week 25. Baseline is considered to be the first dose of tocilizumab treatment. Key conclusions Efficacy in patients who continued on tocilizumab sc was maintained over 49 weeks and remained comparable to that of tocilizumab iv. The week 49 cumulative safety profile of tocilizumab sc was consistent with week 24 data and with those of tocilizumab iv, with the exception of injection-site reactions, which were lower in the tocilizumab-iv group. The efficacy, safety, and pharmacokinetic results in patients who switched from tocilizumab iv to sc and vice versa were comparable to those in patients who remained on tocilizumab sc or iv. There was no correlation between anti-tocilizumab antibody development and clinical responses or adverse events. Tocilizumab sc could provide an additional administration option for patients with RA. Reference: 1.Burmester GR, Rubbert-Roth A, Cantagrel A, et al. The efficacy and safety of tocilizumab subcutaneous versus tocilizumab intravenous, in combination with traditional DMARDS in patients with RA at 49 weeks (SUMMACTA). ACR Annual Meeting Abstracts 2013: New Evidence in Rheumatology March 2014

12 In Supportive Care Oncology Kivitz A, et al. ACR 2013:1428 The BREVACTA study: safety and efficacy of tocilizumab subcutaneous in combination with traditional DMARDs for up to 48 weeks in patients with moderate-to-severe rheumatoid arthritis Background Intravenous (iv) tocilizumab has demonstrated efficacy, with a manageable safety profile, in patients with rheumatoid arthritis (RA) who had an inadequate response to disease-modifying antirheumatic drugs (DMARDs) or tumour necrosis factor inhibitors (TNF-Is); it is currently approved for use in more than 70 countries. The phase III BREVACTA study evaluated the safety and efficacy of subcutaneous (sc) tocilizumab in combination with DMARDs as an additional formulation of tocilizumab, and demonstrated superiority of tocilizumab sc to placebo sc with respect to American College of Rheumatology (ACR) 20 response at week 24. Additionally, tocilizumab sc was well tolerated over 24 weeks, and the adverse event profile was consistent with that of tocilizumab iv. At ACR 2013, Kivitz and colleagues presented long-term data from up to 48 weeks of the BREVACTA study. 1 Study design The study population included adult patients with moderate-to-severe active RA for more than six months at baseline who had: An inadequate response to at least one DMARD; Swollen joint count (SJC) 6 (66-joint count); Tender joint count (TJC) 8 (68-joint count); Either elevated C-reactive protiein ( 1 mg/dl) or erythrocyte sedimentation rate ( 28 mm/h); Radiographic evidence of 1 joint with definite erosion attributable to RA (as measured by the van der Heijde-modified Sharp score) Patients continued on DMARDs, corticosteroids, and nonsteroidal anti-inflammatory drug therapies during the study. Patients were randomized 2:1 to receive tocilizumab sc or placebo sc; patients were stratified by body weight ( 60 kg, kg, or 100 kg) and region at randomization. The dose of tociliuzumab sc was 162 mg every two weeks (q2w) by prefilled syringe. Placebo sc was administered in the same manner. At week 24, patients were re-randomized for the open-label period. All patients were randomized 1:1 to receive tocilizumab sc 162 mg q2w either by prefilled syringe or by autoinjector. Escape therapy: patients who had <20% improvement from baseline in both SJC and TJC between weeks 12 and 48, or who had <70% improvement from baseline in both SJC and TJC after week 48, could receive openlabel tocilizumab sc every week (qw). Patients who received escape therapy remained on tocilizumab sc qw throughout the study. If a patient received escape therapy before week 24, they were not re-randomized. The data presented here only include patients who received tocilizumab sc from baseline onward, regardless of the injection device used. Data from patients who received placebo sc during the doubleblind period or from those who received escape therapy are not presented. Primary endpoint: ACR20 response at week 24. Secondary endpoints: ACR50 and ACR70 responses at week 24; 28-joint disease activity score (DAS28) at week 24; Health assessment questionnaire-disability index (HAQ-DI) at week 24; Radiographic change from baseline at weeks 24 and 48; Major clinical response (ACR70 for 24 weeks) at week 48. Safety endpoints: Adverse events (AEs); Serious AEs (SAEs); Laboratory assessments. New Evidence in Rheumatology March

13 Study design TCZ sc 162 mg q2w + DMARDs (prefilled syringe) TCZ sc 162 mg q2w + DMARDs (prefilled syringe) TCZ sc 162 mg q2w + DMARDs (autoinjector) R Placebo sc q2w + DMARDs (prefilled syringe) Escape therapy: TCZ sc 162 mg qw (Weeks 12 24: PFS, postweek 24: prefilled syringe or autoinjector) TCZ sc 162 mg q2w + DMARDs (prefilled syringe) TCZ sc 162 mg q2w + DMARDs (autoinjector) 24-week double-blind 72-week open-label DMARD = disease-modifying antirheumatic drug; q2w = every 2 weeks; sc = subcutaneous; TCZ = tocilizumab Key findings Baseline characteristics and disposition Patient demographics and clinical characteristics were balanced across the two arms at baseline. 7.8% of patients started treatment with a lipid-lowering agent during the study (who were not receiving one at study entry). Of the 438 patients randomized to the tocilizumab arm, 341 completed to week 24 and 315 completed to week 48. Before week 24, 26 patients withdrew from the study and 71 patients received escape therapy of tocilizumab qw. Between weeks 24 and 48, 20 patients withdrew from the study and six patients received escape therapy of tocilizumab qw. Efficacy Efficacy responses observed at 24 weeks were maintained or improved through 48 weeks. (Figure 1) By week 48, 11% of patients had achieved a major clinical response (defined as maintaining an ACR70 response for 24 weeks). Improvements in ACR core components, disease activity (DAS28), and physical function (HAQ-DI) were maintained through week 48. (Table 1) Reduction in radiographic progression of structural joint damage was also maintained from week 24 to week 48. (Figure 2) Figure 1. Proportions of patients achieving ACR20/50/70 responses (ITT population) TCZ sc q2w + DMARDs (N = 437) 70 Proportion of patients with an ACR response (%) ACR20 ACR50 ACR70 62% 45% 26% Week ACR = American College of Rheumatology; DMARD = disease-modifying antirheumatic drug; ITT = intent to treat; q2w = every 2 weeks; sc = subcutaneous; TCZ = tocilizumab 12 New Evidence in Rheumatology March 2014

14 In Supportive Care Oncology Table 1. Efficacy at baseline, week 24, and week 48 (ITT) Figure 2. Change from baseline in mtss at weeks 24 and 48* (ITT population) TCZ sc q2w + DMARDs TCZ sc q2w + DMARDs (N = 437) Parameter, mean (SD) Baseline Week 24 Week 48 SJC (10.34) 5.40 (7.61) 4.02 (5.81) TJC (14.99) (12.61) 7.47 (10.38) ESR (24.76) (14.53) (12.94) CRP 2.01 (2.62) 0.35 (0.87) 0.30 (0.91) Patient pain VAS (22.75) (22.12) (22.16) Patient global VAS (22.43) (23.56) (22.89) Physician global VAS (17.04) (19.73) (15.43) HAQ-DI score 1.63 (0.62) 1.10 (0.67) 0.98 (0.66) HAQ-DI 0.33, % DAS (0.92) 3.42 (1.48) 2.95 (1.33) DAS28 remission (DAS28 <2.6), % CRP = C-reactive protein; DAS28 = 28-joint disease activity score; DMARD = diseasemodifying antirheumatic drug; ESR = erythrocyte sedimentation rate; HAQ-DI = health assessment questionnaire-disability index; ITT = intent to treat; q2w = every 2 weeks; sc = subcutaneous; SD = standard deviation; SJC66 = 66-joint swollen joint count; TCZ = tocilizumab; TJC68 = 68-joint tender joint count; VAS = visual analog scale placebo sc q2w + DMARDs (baseline to week 24), TCZ sc q2w + DMARDs (weeks 24 to 48) 1.48 Safety The safety profile of tocilizumab sc remained stable over time. (Table 2) Rates of AEs and SAEs remained stable or decreased between weeks 24 and 48. (Table 2) Table 2. Overview of AEs and SAEs at weeks 24 and 48 (safety population) Rate/100 pt-yrs (95% CI) [no. of events] TCZ sc q2w + DMARDs Week 24 Week 48 N Pt-yrs AEs SAEs Serious infections Injection-site reactions Hypersensitivity* Clinically significant hypersensitivity ( ) [803] ( ) [25] 6.57 ( ) [12] ( ) [57] ( ) [25] 1.09 ( ) [2] ( ) [1,472] ( ) [51] 3.81 ( ) [15] ( ) [97] 8.89 ( ) [35] 0.76 ( ) [3] AE = adverse event; CI = confidence interval; DMARD = disease-modifying antirheumatic drug; pt-yrs = patient-years; q2w = every 2 weeks; SAE = serious adverse event; sc = subcutaneous; TCZ = tocilizumab * Hypersensitivity events were defined as occurring within 24 hours of an injection (excluding injection-site reactions) and not unrelated to study medication. Clinically significant hypersensitivity was defined as occurring within 24 hours of an injection (excluding injection-site reactions), not unrelated to study medication, and leading to withdrawal. Mean change in mtss By week 48, 21 patients had withdrawn from tocilizumab sc treatment due to AEs, most commonly infections or elevated liver enzyme levels. Six deaths occurred in the tocilizumab sc group up to week 48: Week 24 Week 48 n = 397 n = 192 n = 398 n = 193 DMARD = disease-modifying antirheumatic drug; ITT = intent to treat; mtss = modified total Sharp score; q2w = every 2 weeks; sc = subcutaneous; TCZ = tocilizumab *Week 48 radiographic data were run on Campaign 2, comprising evaluations of baseline, week 24, week 48, and early withdrawal or escape up to the week 48 visit. As these data have been updated from Campaign 1, there are slight differences to the week 24 results previously reported. The mean (SD) annualized progression rate for patients receiving tocilizumab sc decreased from 0.9 (4.31) from baseline to week 24 to 0.29 (2.75) from week 24 to week 48. Through week 24, three deaths occurred: two due to sepsis and one due to lower respiratory tract infection; From week 24 to 48, three deaths occurred: one due to angina pectoris, one due to acute myocardial infarction, and one due to pyrexia (unknown origin). The most common infections for patients receiving tocilizumab sc were upper respiratory tract infections (11.2%) and nasopharyngitis (7.6%). The most common serious infections for patients receiving tocilizumab sc were sepsis, bacterial arthritis, and lower respiratory tract infections (all <1%). The most frequent injection-site reaction symptoms were erythema (3.0%), pain (2.7%), and pruritus (1.4%). New Evidence in Rheumatology March

15 Three patients experienced clinically significant hypersensitivity events: one with neutropenia, one with weight increase, and one with hypersensitivity. No anaphylaxis or medically confirmed serious hypersensitivity occurred. Seven patients (1.6%) tested positive for immunogenicity at week 24, and 10 patients (2.3%) tested positive at week 48. No patient who tested positive for immunogenicity experienced clinically significant or serious hypersensitivity or withdrew due to insufficient therapeutic response. No patients met the criteria for Hy s Law. Levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides remained stable from week 24 to week 48. Key conclusions Tocilizumab sc demonstrated long-term efficacy, including sustained ACR response rates and reduced progression of joint damage over 48 weeks. There was no change in the AE profile for tocilizumab sc compared with earlier evaluations, and the safety profile remained consistent with that of tocilizumab iv. Tocilizumab sc is an effective treatment in RA and will offer an alternative route of administration, and the possibility of self-administration. Reference: 1. Kivitz A, Olech E, Borofsky M, et al. The safety and efficacy of tocilizumab subcutaneous in combination with traditional DMARDs in patients with moderate to severe rheumatoid arthritis up to 48 weeks (BREVACTA). ACR Annual Meeting Abstracts 2013:1428. Gabay C, et al. ACR 2013:450 Tocilizumab monotherapy compared with adalimumab monotherapy in patients with rheumatoid arthritis: an evaluation of high-density lipoprotein composition Background Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease (CVD). Although analyses of lipids (such as low-density lipoprotein cholesterol [LDL-C] and high-density lipoprotein cholesterol [HDL-C]) are useful for estimating CVD risk in the general population, they may not describe the complete picture in RA patients, in whom disease-associated inflammation is associated with low HDL-C and altered HDL composition (resulting in an atherogenic phenotype). Reduction of inflammation leads to a restoration of the atheroprotective phenotype of HDL (Figure 1). The objective of this study was to investigate changes in HDL composition in RA patients after 8 weeks of treatment with the interleukin-6 receptor inhibitor tocilizumab, or the tumour necrosis factor-α inhibitor adalimumab, administered as monotherapy. 1 Study design The ADACTA study was a randomized, doubleblind, phase IV study in 326 patients with RA: Tocilizumab 8 mg/kg intravenously every 4 weeks for 24 weeks: n = 163; Adalimumab 40 mg subcutaneously every 2 weeks for 24 weeks: n = 163. Both treatments were administered as monotherapy. Analysis of HDL composition included patients from the ADACTA study who donated serum bio-repository samples at baseline and at week 8 (tocilizumab: n = 87; adalimumab: n = 97). Lipid changes in both groups stabilized by week 8, whereas American College of Rheumatology (ACR) responses were not stable until week 24. Therefore, week 8 samples were selected for lipid evaluation, and week 24 efficacy data were used in this analysis. 14 New Evidence in Rheumatology March 2014

16 In Supportive Care Oncology Figure 1. Changes in cardiovascular inflammatory markers on treatment of patients with RA Increased inflammation Atherogenic HDL spla 2 HDL-SAA apoj apoa1 PON-1 PAF-AH LCAT CETP Treatment of patients with RA Altered HDL particle composition apoa1 = apolipoprotein A1; apoj = apolipoprotein J; CETP = cholesteryl ester transfer protein; HDL = high-density lipoprotein; HDL-SAA = high-density lipoprotein-serum amyloid A; LCAT = lecithin-cholesterol acyltransferase; PAF-AH = platelet-activating factor acetylhydrolase; PON-1 = paraoxonase-1; RA = rheumatoid arthritis; spla 2 = secretory phospholipase A 2 Changes from baseline to week 8 in median high-density lipoprotein serum amyloid A (HDL-SAA) and secretory phospholipase A 2 (spla 2 ) levels were evaluated using nonparametric Kruskal-Wallis analyses to test for differences in medians between treatment groups and to compare the change in HDL-SAA and spla 2 between ACR20 responders and nonresponders at week 24. Reduced inflammation Atheroprotective HDL Spearman rank correlation coefficients were used to determine associations among changes in HDL-SAA, spla 2, C-reactive protein (CRP), and apolipoprotein A1 (apoa1) levels. apoa1 PON-1 PAF-AH LCAT CETP spla 2 HDL-SAA apoj Key findings Baseline characteristics and disposition Baseline parameters were balanced across treatment groups with the exception of lipid-lowering agent use, which was slightly higher in the adalimumab group (adalimumab, tocilizumab): Mean age (years): 54.3, 53.4; Sex (male/female, %): 23/77, 21/79; Mean weight (kg): 79.2, 77.8; Geographic region (North America/other, %): 34/66, 45/55; Oral corticosteroid use (%): 51, 48; Lipid-lowering agent use (%): 18, 13; Rheumatoid factor-positive (%): 70, 68; Anti-cyclic citrullinated peptide-positive (%): 69, 70; Mean duration of RA (years): 6.7, 6.8; Mean 68-joint tender joint count: 29.5; 27.7; Mean 66-joint swollen joint count: 16.8, 16.2; Mean 28-joint disease-activity score-erythrocyte sedimentation rate: 6.78, No changes were made to lipid-lowering agents during the study. Efficacy Changes in lipid parameters and CRP in this patient population were consistent with those observed in previous studies with adalimumab and tocilizumab. (Table 1) Table 1. Changes in lipids and inflammatory markers from baseline to week 8* ADA (n = 97) TCZ (n = 87) Baseline Week 8 Mean change from baseline (SD) Baseline Week 8 Mean change from baseline (SD) LDL-C, mm 2.84 n = n = (0.53) n = n = n = (0.74) n = 75 HDL-C, mm 1.53 n = n = (0.26) n = n = n = (0.30) n = 77 LDL/HDL 1.97 n = n = (0.46) n = n = n = (0.56) n = 75 apoa1, mg/ml 1.4 n = n = (0.22) n = n = n = (0.22) n = 79 apob/apoa n = n = (0.13) n = n = n = (0.14) n = 79 CRP, mg/l 2.59 n = n = (3.29) n = n = n = (3.74) n = 49 ADA = adalimumab; apoa1 = apolipoprotein A1; apob = apolipoprotein B; CRP = C-reactive protein; HDL = high-density lipoprotein; HDL-C = HDL cholesterol; LDL = low-density lipoprotein; LDL-C = LDL cholesterol; SD = standard deviation; TCZ = tocilizumab *Data are available for patients who provided both baseline and week 8 samples. New Evidence in Rheumatology March

17 Increases in HDL-C and LDL-C at week 8 compared with baseline were observed after treatment with both adalimumab and tocilizuamb; these changes were greater with adalimumab than with tocilizumab. However, no changes were observed in the apob/apoa1 ratio in either treatment group. (Table 1) Reductions in HDL-SAA and spla 2 were observed in both treatment groups, with a greater treatment effect seen with tocilizumab (p <0.05). (Table 2) Differences in mean and median results indicated data were not normally distributed; therefore nonparametric methods were appropriate for analyzing these data. A difference in favour of tocilizumab was also observed when ACR20 responders and nonresponders were evaluated: (Figure 2) Among ACR 20 responders, reductions in HDL-SAA and spla 2 were greater with tocilizumab than with adalimumab (p <0.05); Reductions in HDL-SAA for ACR20 responders mirrored those for the nonresponder groups; Reductions in spla 2 were smaller for ACR20 nonresponders than for responders in both treatment groups; Reductions in HDL-SAA and spla 2 were numerically greater with tocilizumab for both ACR20 responders and nonresponders. Moderate positive correlation was observed between HDL- SAA and spla 2 in each treatment group. (Table 3) Stronger correlations were noted between HDL-SAA and CRP and between spla 2 and CRP. (Table 3) Weak negative correlations between HDL-SAA or spla 2 and apoa1 were found with tocilizumab, and weaker correlations were found with adalimumab. (Table 3) Table 2. Change from baseline to week 8 in HDL-SAA and spla 2 Subgroup All patients Statistic Change from baseline to week 8 in HDL-SAA, mg/l Change from baseline to week 8 in spla 2, ng/ml ADA TCZ ADA TCZ n Mean (SD) 4.4 (12.3) 9.3 (18.3) 1.8 (9.2) 7.8 (12.8) Median (min, max) Quartiles (25%, 75%) 1.1 ( 42.4, 26.5) 3.2 ( 112.6, 9.1) 1.3 ( 43.8, 29.7) 4.1 ( 70.6, 1.6) 7.1, , , , 1.1 p* < ADA = adalimumab; HDL-SAA = high-density lipoprotein-serum amyloid A; SD = standard deviation; spla 2 = secretory phospholipase A 2 ; TCZ = tocilizumab *p values refer to comparisons between medians using the Kruskal-Wallis test (ADA vs. TCZ). Figure 2. Change from baseline to week 8 in HDL-SAA and spla 2 for ACR20 responders and nonresponders at week 24 4 ACR20 = yes ACR20 = no 4 ACR20 = yes ACR20 = no Change in HDL-SAA, mg/l (median, IQR) Change in spla 2, ng/ml (median, IQR) ADA (n = 32) TCZ (n = 39) ADA (n = 30) TCZ (n = 16) ADA (n = 47) TCZ (n = 52) ADA (n = 39) TCZ (n = 21) ACR = American College of Rheumatology; ADA = adalimumab; HDL-SAA = high-density lipoprotein-serum amyloid A; IQR = interquartile range; spla 2 = secretory phospholipase A 2 ; TCZ = tocilizumab 16 New Evidence in Rheumatology March 2014

18 In Supportive Care Oncology Table 3. Correlations between acute-phase reactants and cargo protein levels spla 2 CRP apoa1 TCZ HDL-SAA r = 0.57 p < spla 2 r = 0.58 p < r = 0.66 p < r = 0.27 p = 0.05 r = 0.25 p = 0.04 ADA HDL-SAA r = 0.54 p < spla 2 r = 0.69 p < r = 0.74 p < r = 0.19 p = 0.13 r = 0.16 p = 0.14 ADA = adalimumab; apoa1 = apolipoprotein A1; CRP = C-reactive protein; HDL-SAA = high-density lipoprotein-serum amyloid A; spla 2 = secretory phospholipase A 2 ; TCZ = tocilizumab Key conclusions The observed reductions in HDL-SAA and spla 2 suggest that tocilizumab, to a greater extent than adalimumab, changes HDL composition toward a more atheroprotective profile. Reductions in HDL-SAA and spla 2 were noted for both ACR20 responders and nonresponders, which suggested a beneficial effect of biologic therapy on HDL composition regardless of therapeutic response. The strongest correlation was observed between CRP and HDL-SAA or spla 2, which is consistent with the acute-phase response. These data suggest that clinicians may have to measure HDL cargo proteins to fully understand the RA patient risk profile and the potential risk reduction of therapeutics. Reference: 1. Gabay C, Tuckwell K, Green J, et al. Tocilizumab monotherapy compared with adalimumab monotherapy in patients with rheumatoid arthritis: an evaluation of high-density lipoprotein composition. ACR Annual Meeting Abstracts 2013:450. Genovese MC, et al. ACR 2013:459 Transaminase levels and hepatic events observed during tocilizumab treatment: pooled analysis of long-term clinical trial safety data in patients with rheumatoid arthritis Background In human hepatocytes, interleukin (IL)-6, in conjunction with IL-1, tumour necrosis factor (TNF)-α, and other cytokines, is the major regulator of the synthesis of acute-phase proteins during inflammation. Tocilizumab is an IL-6 receptor monoclonal antibody that is approved for the treatment of patients with rheumatoid arthritis (RA). Elevated hepatic transaminase levels have been reported during tocilizumab treatment of RA patients for whom dose modification or interruption has been recommended. The purpose of this study was to examine the effect of intravenous (iv) tocilizumab on hepatic transaminase levels and to evaluate hepatic serious adverse events (SAEs) observed in a long-term clinical program. 1 Study design All-exposure population: analyses were performed in all patients who received one dose of tocilizumab 4 or 8 mg/kg in any of five phase III, placebo-controlled studies (OPTION, TOWARD, RADIATE, AMBITION, LITHE), a clinical pharmacology study, a phase IV tocilizumab monotherapy study (ADACTA), or long-term extension studies (GROWTH95, GROWTH96, LITHE extension phase). Data were pooled and analyzed from initial tocilizumab exposure to May 2, Placebo-controlled population: included data from patients who received one dose of tocilizumab 4 or 8 mg/kg during the double-blind treatment New Evidence in Rheumatology March

19 phase of the five phase III placebo-controlled studies, pooled by patient population: disease-modifying antirheumatic drug-inadequate response (DMARD-IR) (LITHE, OPTION, TOWARD), TNF-IR (RADIATE), and methotrexate-naïve (subgroup of patients from AMBITION). Data were included from randomization until the first change in treatment, or until one-year study duration (LITHE) was reached. Methotrexate-intolerant or inappropriate-for-methotrexate population: included data from patients who received tocilizumab 8 mg/kg in the double-blind, active-controlled ADACTA study. Exclusion criteria: Alanine transaminase (ALT) or aspartate transaminase (AST) levels >1.5x upper limit of normal (ULN); Known active current or history of recurrent hepatitis B and C; History of alcohol or chemical abuse during the six months before screening; Evidence of serious uncontrolled concomitant hepatic disease; Current hepatic disease as determined by the principal investigator. Adverse event (AE) rates were calculated as the total number of AEs divided by the total patient-years (pt-yrs) duration and expressed per 100 pt-yrs with a 95% confidence interval (CI). ALT/AST levels were measured at baseline, every two weeks until week 16 (except week 10), then every four weeks in the phase III double-blind studies and every 12 weeks in the extension studies until the cutoff date; in the ADACTA study, ALT/AST levels were measured at baseline and every two weeks throughout the study. DMARD and tocilizumab doses were to be modified for ALT/ AST elevations. Recommendations in the protocols were the same or similar to those in the U.S. prescribing information for tocilizumab. Patients withdrawn from the study for elevated ALT/AST levels were followed up until levels returned to baseline. Hepatic SAE incidence rates were estimated from the U.S.-based Truven Health MarketScan health care claims database and the literature. Hepatic SAEs were defined on the basis of the International Classification of Diseases, Ninth Revision, Clinical Modification. Key findings Patient characteristics All-exposure population: A total of 4,171 patients received tocilizumab, alone or in combination with methotrexate or another DMARD, and had one postbaseline safety assessment; Mean (median [range]) duration of exposure to tocilizumab: 3.9 years (5.1 [ ]); Observation time: 16,204.8 pt-yrs; Predominantly female (81.9%) and white (74.7%); Mean age (range): 52.1 years (18 89); Concomitant methotrexate use: 76% (mean dose at baseline: 15.2 mg/week); Mean methotrexate dose at week 156: 15.3 mg/week. Placebo-controlled population: A total of 2,644 patients received tocilizumab (observation time: 1,560 pt-yrs); A total of 1,454 patients received placebo/methotrexate/ DMARD (observation time: 743 pt-yrs). Methotrexate-intolerant or inappropriate-for-methotrexate population: A total of 162 patients received tocilizumab (observation time: 69 pt-yrs). Patterns of ALT/AST elevations In the all-exposure population, 92.2%/95.2% of patients, respectively, had ALT/AST levels within the normal range at baseline. Mean and median ALT/AST levels increased within the normal range after tocilizumab initiation and remained stable at the higher level thereafter. ALT/AST levels increased from normal at baseline to >ULN at least once in 70.6% and 59.4% of patients with available baseline and postbaseline values, respectively, during the study period. In most of these patients, the highest postbaseline value was >1 3x ULN; ALT/AST elevations to >5x ULN occurred in 2.9% and 0.9% of patients, respectively. (Figure 1) In the all-exposure population, analysis showed that the proportion of ALT elevations was highest during the first 12 months, and no evidence was found of an increased risk of elevation over time. (Figure 2) Elevations in ALT/AST >ULN during the first 12 months of tocilizumab treatment conferred an increased likelihood of subsequent elevations to >1x ULN and >3x ULN during each subsequent 12-month period analyzed, compared with patients with ALT/AST 1x ULN during the first 12 months. During months 13 to 24, incidences of ALT/AST elevations to >1x ULN and >3x ULN were 63.9% and 5.4%, respectively, for patients with one value of ALT/AST >ULN during the first 12 months, compared with 24.0% and 0.6%, respectively, for patients with ALT/AST values within the reference range in the first 12 months. 18 New Evidence in Rheumatology March 2014

20 In Supportive Care Oncology Figure 1. Summary of shifts in ALT/AST levels (all-exposure population) Normal >1 3x ULN >3 5x ULN >5x ULN 3.3 (n = 129) AST* (n = 3,965) 40.5 (n = 1,608) 55.3 (n = 2,194) 8.9 (n = 341) 0.9 (n = 34) ALT (n = 3,839) 29.4 (n = 1,127) 58.8 (n = 2,258) 2.9 (n = 113) Patients (%) 100 ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal *AST ULN = 40 U/L. ALT ULN = 55 U/L. Figure 2. All occurrences of ALT elevations over time* Normal >1 3x ULN >3 5x ULN >5x ULN Patients (%) N Normal >1 3x ULN >3 5x ULN >5x ULN Months 4,163 3,441 3,091 2,867 2,682 2, ,782 1,846 1,755 1,701 1,621 1, ,076 1,475 1,235 1, ALT = alanine aminotransferase; ULN = upper limit of normal *Each 12-month period was assessed independently; the highest ULN category within a 12-month period was selected; ALT ULN = 55 U/L. New Evidence in Rheumatology March

21 ALT/AST increases >3x ULN were single occurrences in most patients; at most, 0.2% of patients sustained elevations in ALT/AST during any 12-month period. (Table 1) Tocilizumab monotherapy versus combination therapy ALT/AST elevations occurred more frequently in patients who received tocilizumab in combination with methotrexate/dmards than in patients who received tocilizumab monotherapy. (Table 2) Data for this comparison in ALT/AST elevations were taken from the placebo-controlled population and the ADACTA trial, where DMARD use was controlled. Safety ALT/AST elevation AEs resulted in 105 of 4,171 patients (2.5%) prematurely withdrawing from the study; most withdrawals occurred within the first 12 months of treatment (77/105 patients). At the time of data cutoff, 78% of ALT/AST elevations >3x ULN had returned to normal. Similar proportions of patients had normalization of ALT/AST levels with and without tocilizumab therapy interruption. Median time to observed ALT/AST normalization was six weeks. Table 1. Patterns of ALT/AST elevations >3x ULN by 12-month periods 0 12 months, n (%) months, n (%) months, n (%) months, n (%) months, n (%) months, n (%) months, n (%) ALT* n = 4,163 n = 3,440 n = 3,091 n = 2,867 n = 2,682 n = 2,381 n = 973 Single 180 (4.3) 86 (2.5) 70 (2.3) 54 (1.9) 53 (2.0) 32 (1.3) 9 (<0.1) Consecutive 59 (1.4) 19 (0.6) 15 (0.5) 18 (0.6) 6 (0.2) 10 (0.4) 0 Sustained 4 (0.1) 1 (<0.1) 5 (0.2) 1 (<0.1) 3 (0.1) 1 (<0.1) 0 Nonconsecutive** 62 (1.5) 14 (0.4) 11 (0.4) 13 (0.5) 8 (0.3) 6 (0.3) 0 AST n = 4,163 n = 3,437 n = 3,090 n = 2,867 n = 2,682 n = 2,380 n = 967 Single 81 (1.9) 28 (0.8) 29 (0.9) 21 (0.7) 12 (0.4) 13 (0.5) 6 (<0.1) Consecutive 7 (0.2) 6 (0.2) 0 2 (0.1) 1 (<0.1) 2 (0.1) 0 Sustained (0.1) 1 (<0.1) 0 Nonconsecutive** 4 (0.1) 6 (0.2) 3 (0.1) 3 (0.1) 0 1 (<0.1) 1 (<0.1) ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal *ALT ULN = 55 U/L. Single elevation is defined as only one elevation during the 12-month period analyzed. Consecutive elevation is defined as elevation for 2 consecutive samples during the 12-month period analyzed. Sustained elevation is defined as elevation from the time of first elevation to last record, when the last record reports the last data available, or the end of the 12-month period analyzed. **Nonconsecutive elevation is defined as elevation for 2 nonconsecutive samples during the 12-month period analyzed. AST ULN = 40 U/L. Table 2. Frequency of transaminase elevations in tocilizumab monotherapy vs. combination therapy Normal to >1 3x ULN Normal to >3 5x ULN Normal to >5x ULN ALT AST ALT AST ALT AST Intolerance to MTX or continued MTX use considered inappropriate (ADACTA)* n = 162, % (n) 27.2 (44/162) 24.1 (39/162) 1.2 (2/162) 1.2 (2/162) 1.2 (2/162) 0 TCZ Monotherapy MTX naïve (AMBITION subset) n = 193, % (n) 36.0 (64/178) 20.0 (38/190) 1.1 (2/178) (1/178) 0.5 (1/190) TCZ in combination with MTX/DMARDs DMARD-IR (TOWARD, OPTION, LITHE) n = 2,018, % (n) 48.5 (901/1,858) 40.6 (779/1,921) 4.8 (89/1,858) 1.6 (31/1,921) 1.6 (30/1,858) 0.2 (3/1,921) TNF-IR (RADIATE) n = 338, % (n) 35.1 (110/313) 30.3 (98/323) 2.6 (8/313) 0.3 (1/323) 0.6 (2/313) 0 ALT = alanine aminotransferase; AST = aspartate aminotransferase; DMARD = disease-modifying antirheumatic drug; IR = inadequate response; MTX = methotrexate; TCZ = tocilizumab; TNF = tumour necrosis factor; ULN = upper limit of normal *MTX-intolerant or inappropriate-for-mtx population. Placebo-controlled population. The AMBITION subset was a subset of patients in the AMBITION study who received tocilizumab therapy. Shifts from normal at baseline to highest postbaseline value are shown. Only patients who had normal ALT/AST at baseline and a valid baseline and 1 postbaseline result are included. 20 New Evidence in Rheumatology March 2014

22 In Supportive Care Oncology Seven cases of hepatic SAEs were reported (0.04/100 pt-yrs [95% CI: ]); events were variable in nature with no pattern over time. (Table 3) No hepatic SAEs were reported during the placebocontrolled periods. The rate of hepatic SAEs in tocilizumab-treated patients was consistent with the available background rates of hepatic SAEs or hospitalizations estimated for RA patients treated with other biologics and conventional DMARDs. In the MarketScan claims database analysis: Incidence rates of hepatic SAEs in all RA patients, patients treated with TNF antagonists, and patients treated with methotrexate were 0.09 (95% CI: ), 0.07 (95% CI: ), and 0.07 (95% CI: ) events/100 pt-yrs, respectively. A number of factors, including concomitant medications and comorbidities, were not controlled for in this analysis. This should be taken into consideration when interpreting these data. Table 3. Details of hepatic serious adverse events (all-exposure population) Age, years/sex RA duration Event Event outcome Action taken with TCZ 58/F 7 months Hepatic cirrhosis 59/F 10 years 59/F 10 months 73/F 16 years 53/F 18 years Worsening autoimmune hepatitis Acute hepatic failure due to portal vein and hepatic vein thromboses Ascites of unknown etiology Ischemic hepatitis due to anaphylaxis 62/F 31 years Hepatic steatosis 45/F 1 year Hepatitis Unresolved at last contact Unresolved at last contact Concomitant/ previous medication Medical history Discontinued MTX None reported Discontinued MTX; previous: leflunomide Death N/A MTX Resolved without sequelae Resolved without sequelae Unresolved at last contact Resolved without sequelae Autoimmune hepatitis; hypertension Positive anticardiolipin IgG; hypertension; smoking Dose modified MTX Hypertension Discontinued Methylprednisolone Hypertension Discontinued Hypertension Discontinued ~2 months before event F = female; IgG = immunoglobulin G; MTX = methotrexate; N/A = not available; TCZ = tocilizumab; RA = rheumatoid arthritis MTX Hypertension Key conclusions Mean ALT/AST levels increased early in tocilizumab treatment, and the proportion of patients with elevations did not increase with continued tocilizumab exposure. In most patients, ALT/AST elevations were 3x ULN; ALT/AST elevations to >5x ULN occurred in 2.9% and 0.9% of patients, respectively. Most elevations >3x ULN were single occurrences. Liver enzyme monitoring is recommended in patients being treated with tocilizumab; transaminase elevations are managed with tocilizumab and/or DMARD dose modification or interruption. The rate of hepatic SAEs observed in patients treated with tocilizumab was similar to the rates in epidemiologic studies of RA patients treated with other biologic and conventional DMARDs. Reference: 1. Genovese MC, Kremer J, van Vollenhoven RF, et al. Transaminase levels and hepatic events observed during tocilizumab treatment: pooled analysis of long-term clinical trial safety data in patients with rheumatoid arthritis. ACR Annual Meeting Abstracts 2013:459. New Evidence in Rheumatology March

23 Buckley F, et al. ACR 2013:460 Comparative efficacy of novel disease-modifying antirheumatic drugs (DMARDs) as monotherapy and in combination with methotrexate in rheumatoid arthritis patients with an inadequate response to traditional DMARDs: a network meta-analysis Background Patients with rheumatoid arthritis (RA) who are intolerant of or who show inadequate response (IR) to traditional disease-modifying antirheumatic drugs (DMARDs) are often treated with a biologic agent in combination with traditional DMARDs. However, onethird of RA patients receiving biologics receive them as monotherapy. A number of meta-analyses indirectly compare the efficacy of biologics for RA; however, comparisons of the efficacy of biologics as monotherapy versus combination therapy with DMARDs are rare, and none include all currently approved biologics and tofacitinib (together referred to here as novel DMARDs). The objective of this study was to compare American College of Rheumatology (ACR) responses to novel DMARDs, as monotherapy or in combination with methotrexate, in RA patients with IR to traditional DMARDs. 1 Study design MEDLINE and EMBASE databases were searched for articles published in English, from January 1990 to April 2013, according to a predefined search strategy. The relevance of each citation and subsequent fulltext report was assessed according to predefined selection criteria: Population: adult RA patients who responded inadequately or for whom treatment with traditional DMARDs failed, as defined in each trial; Intervention: novel DMARDs, at their recommended dose, as monotherapy or in combination; Comparator: any placebo or active intervention; Outcome: ACR20/50/70 response at 24 weeks; Study design: randomized controlled trials. Bayesian network meta-analysis models were used to synthesize the results of the included studies and simultaneously obtain the effect estimates of the novel DMARDs in their usual dose, alone and combined with methotrexate, in terms of ACR20/50/70 responses at 24 weeks compared with placebo. Treatment effects were presented as relative response along with a 95% credible interval (95% CrI), reflecting the range of true estimates with 95% probability. It was assumed that the different anti-tumour necrosis factor (TNF-I) agents have similar efficacy, as demonstrated previously. Therefore, TNF-I data were pooled and considered a treatment class. Thirty studies were included in the analysis. (Figure 1) Figure 1. Evidence network* TNF-I 4 Placebo TCZ TCZ sc + MTX 1 TCZ + MTX 2 TOFA + MTX 3 Placebo + MTX TNF-I + MTX 1 1 ABT + MTX 1 ABT sc + MTX TOFA 1 ANA + MTX ABT = abatacept; ANA = anakinra; MTX = methotrexate; sc = subcutaneous; TCZ = tocilizumab; TNF-I = tumour necrosis factor inhibitor; TOFA = tofacitinib *Numbers refer to available direct comparisons of the 30 included studies. 22 New Evidence in Rheumatology March 2014

24 In Supportive Care Oncology Key findings Despite some variation in patient characteristics across studies (e.g., duration of disease), no systematic differences were observed across the different types of comparisons, indicating the feasibility of the indirect comparison. TNF-I + methotrexate, tofacitinib + methotrexate, abatacept intravenous (iv)/subcutaneous (sc) + methotrexate, and tocilizumab iv/sc + methotrexate demonstrated comparable ACR responses, whereas anakinra + methotrexate was less efficacious. (Figure 2) Among biologic monotherapies, greater ACR20/50/70 responses were observed with tocilizumab than with TNF-I or tofacitinib. (Table 1) ACR20/50/70 responses observed with tocilizumab monotherapy were similar to those observed with tocilizumab + methotrexate. (Table 2) Figure 2. Treatment effects for combination therapies relative to placebo* ABT iv + MTX ACR20 ACR50 ACR70 ABT sc + MTX ANA + MTX TNF-I + MTX TOFA + MTX TCZ iv + MTX TCZ sc + MTX OR vs. placebo + MTX ABT = abatacept; ACR = American College of Rheumatology; ANA = anakinra; CrI = credible interval; iv = intravenous; MTX = methotrexate; OR = odds ratio; sc = subcutaneous; TCZ = tocilizumab; TNF-I = tumour necrosis factor inhibitor; TOFA = tofacitinib *Data are presented as odds ratio + 95% CrI. Table 1. Treatment effects for monotherapies Odds ratio (95% CrI) ACR20 ACR50 ACR70 TNF-I vs. placebo 6.52 ( ) 6.78 ( ) ( ) TOFA vs. placebo 4.75 ( ) 4.94 ( ) 3.78 ( ) TCZ vs. placebo ( ) ( ) ( ) TCZ vs. TNF-I 1.87 ( ) 2.41 ( ) 2.31 ( ) TCZ vs. TOFA 2.58 ( ) 3.34 ( ) 7.34 ( ) TOFA vs. TNF-I 0.72 ( ) 0.73 ( ) 0.32 ( ) ACR = American College of Rheumatology; CrI = credible interval; TCZ = tocilizumab; TNF-I = tumour necrosis factor inhibitor; TOFA = tofacitinib New Evidence in Rheumatology March

25 Greater ACR20/50/70 responses were observed with TNF-I + methotrexate than with TNF-I monotherapy. (Table 2) Sensitivity analyses showed conflicting results for tofacitinib monotherapy versus tofacitinib + methotrexate. (Table 2) Table 2. Monotherapies relative to combination therapies TNF-I vs. TNF-I + MTX TOFA vs. TOFA + MTX TCZ vs. TCZ + MTX Probabilities of ACR20/50/70 response by treatment at 24 weeks are shown in Figure 3. Discussion Odds ratio (95% CrI) ACR20 ACR50 ACR ( ) 0.32 ( ) 0.72 ( ) 0.45 ( ) 0.27 ( ) 0.13 ( ) 0.96 ( ) 0.78 ( ) 1.03 ( ) ACR = American College of Rheumatology; CrI = credible interval; MTX = methotrexate; TCZ = tocilizumab; TNF-I = tumour necrosis factor inhibitor; TOFA = tofacitinib Three rituximab trials were not included in the analysis because its label is restricted to patients with an IR to TNF-Is. Five randomized controlled trials evaluating the efficacy of biologics were excluded from the analysis because they were not considered comparable with the other studies: TEMPO: DMARD-IR but the majority of this patient population was methotrexate-naïve (unlike all included studies) and, as such, was excluded; Combe 2006: only sulfasalazine background therapy was used; Genovese 2008, Weinblatt 2012, Yazici 2012: background DMARD therapy was not limited to methotrexate. Any DMARD or, in some circumstances, multiple DMARDs were permitted. Randomization holds within trials but not across trials. Although systematic differences in patient characteristics were not observed, the risk of unmeasured differences, and therefore, possible bias, was always present in the indirect comparisons. Adjustment for differences in placebo response across the TNF-I trials resulted in similar treatment effects for the TNF-Is. This supports the approach to consider the different TNF-Is as a single class. Since the TNF-I results were pooled (with a random effects model), adjustment for differences in placebo response was not necessary to obtain a valid indirect comparison with other classes of biologics. Figure 3. ACR20/50/70 responses at 24 weeks ACR20 ACR50 ACR70 Probability of response (%) PBO TNF-I TOFA TCZ PBO + MTX ABT iv + MTX ABT sc + MTX ANA + MTX TNF-I + MTX TOFA + MTX TCZ iv + MTX TCZ sc + MTX ABT = abatacept; ACR = American College of Rheumatology; ANA = anakinra; CrI = credible interval; iv = intravenous; MTX = methotrexate; PBO = placebo; sc = subcutaneous; TCZ = tocilizumab; TNF-I = tumour necrosis factor inhibitor; TOFA = tofacitinib *Error bars represent 95% CrI. 24 New Evidence in Rheumatology March 2014

26 In Supportive Care Oncology Key conclusions Based on a network meta-analysis involving indirect comparison of trial findings, the following observations can be made for RA patients with DMARD-IR: Subcutaneous and iv formulations of abatacept and tocilizumab have comparable efficacy. Tocilizumab + methotrexate has efficacy comparable with that of other novel DMARDs + methotrexate. Tocilizumab monotherapy is associated with a larger ACR response than is seen with TNF-Is or tofacitinib. TNF-I monotherapy is likely to show a lower ACR response than that for TNF-I + methotrexate. The response to tocilizumab monotherapy is similar to the response of tocilizumab + methotrexate. Reference: 1. Buckley F, Finckh A, Huizinga TWJ, et al. Comparative efficacy of novel disease-modifying antirheumatic drugs as monotherapy and in combination with methotrexate in rheumatoid arthritis patients with an inadequate response to traditional disease-modifying antirheumatic drugs: a network meta-analysis. ACR Annual Meeting Abstracts 2013:460. Burmester GR, et al. ACR 2013:2767 Tocilizumab in combination therapy and monotherapy versus methotrexate in methotrexate-naïve patients with early rheumatoid arthritis: clinical and radiographic outcomes from a randomized, placebo-controlled trial Background Long-term clinical and radiographic benefits can be achieved for patients with rheumatoid arthritis (RA) with early, efficacious treatment. Recommendations support intensive treatment of patients with severe early RA who exhibit features of poor prognosis. Tocilizumab has demonstrated efficacy and safety for the treatment of RA in phase III randomized controlled trials. The purpose of the FUNCTION study was to evaluate both clinical and radiographic efficacy of tocilizumab in combination with methotrexate and as monotherapy in patients with early RA. 1 Study design Primary endpoint: Efficacy, as defined by a 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR) remission (<2.6) at week 24. Secondary endpoints: Prevention of structural joint damage, as evaluated by the van der Heijde modified Total Sharp Score (VdH mtss); Improvement in physical function, as evaluated by the health assessment questionnaire-disability index (HAQ-DI); Safety of tocilizumab in patients with early RA. Patients were randomized 1:1:1:1 to one of the following groups: Placebo + methotrexate (MTX); Tocilizumab 4 mg/kg + methotrexate (TCZ4 + MTX); Tocilizumab 8 mg/kg + methotrexate (TCZ8 + MTX); Tocilizumab 8 mg/kg + placebo (TCZ8 monotherapy). Patients received blinded treatment for two years. Key inclusion criteria included: Adults with RA 2 years in duration; DAS28 >3.2; Methotrexate naïve; ESR 28 mm/h or C-reactive protein 1 mg/dl; Rheumatoid factor-positive or anti-cyclic citrullinated peptide-positive, or 1 joint erosion; Oral corticosteroids permitted ( 10 mg/d prednisone or equivalent). New Evidence in Rheumatology March

27 Study design Screening (3 weeks) Year 1: blinded treatment Year 2: blinded treatment A total of 139 patients withdrew from the study before week 24, and a further 103 patients withdrew between weeks 24 and 52. The number of withdrawals was balanced between treatment groups. Treated (N = 1,157) Randomization (1:1:1:1) Key findings Baseline characteristics and disposition Patient demographics and baseline disease characteristics were well balanced between groups. Of note is the short mean duration of RA in these patients, which ranged from 0.4 to 0.5 years. Of the 1,162 patients enrolled in the study, 1,157 comprised the intent-to-treat population and 1,153 comprised the safety population. Placebo + MTX* (MTX) TCZ 8 mg/kg + MTX* (TCZ8 + MTX) TCZ 8 mg/kg + placebo (TCZ8 monotherapy) TCZ 4 mg/kg + MTX* (TCZ4 + MTX) Baseline Week 24 (Primary endpoint: Week 52 (Primary data cutoff) DAS28 remission at week 24) TCZ/placebo intravenous infusion every four weeks Radiographs at weeks 0, 24, 52, 104. DAS28 = 28-joint disease activity score; MTX = methotrexate; TCZ = tocilizumab *MTX dose: 7.5 to 20 mg weekly (week 0 3: 7.5 mg/week; week 4 7: 15 mg/week; week 8 onward: 20 mg/week). Rescue: MTX and TCZ4 + MTX were increased to TCZ8 + MTX if DAS at week 52. Week 104 Efficacy The percentages of patients who achieved DAS28-ESR remission (<2.6) at both week 24 and week 52 were greater in all tocilizumab groups compared with those in the MTX group. (Figure 1) ACR20/50/70 responses at week 24: A higher proportion of patients achieved ACR20/50/70 responses in the TCZ8 + MTX group (75%/57%/39%) compared with those in the MTX group (65%/43%/25%). The TCZ4 + MTX group achieved higher rates of ACR20 and 70 responses (74% and 35%, respectively) compared with those in the MTX group. ACR20/50/70 responses at week 52: A higher proportion of patients achieved ACR20/50/70 responses in the TCZ8 + MTX group (67%/56%/43%) compared with those in the MTX group (57%/41%/29%). The TCZ4 + MTX group achieved higher rates of ACR50 and 70 responses (52% and 37%, respectively) compared with those in the MTX group. The TCZ8 monotherapy group achieved a higher rate of ACR50 response (49%) compared with that in the MTX group. All tocilizumab groups had significantly higher rates of clinical disease activity index (CDAI) remission ( 2.8) (TCZ8 + MTX: 25%; TCZ4 + MTX: 22%; TCZ8 monotherapy: 21%) at 24 weeks compared with that in the MTX group (13%). Figure 1. Primary endpoint: DAS28-ESR remission (ITT population) Patients with DAS28-ESR <2.6 (%) * 45 * * MTX (N = 287) TCZ8 + MTX (N = 290) TCZ8 monotherapy (N = 292) TCZ4 + MTX (N = 288) 0 Week 24 Week 52 DAS28-ESR = 28-joint disease activity score-erythrocyte sedimentation rate; ITT = intent to treat; MTX = methotrexate; TCZ = tocilizumab *p < (vs. MTX). p < (vs. MTX), but tested after the hierarchichal chain was broken. 26 New Evidence in Rheumatology March 2014

28 In Supportive Care Oncology At week 52, only the TCZ8 + MTX group had a significantly higher rate of CDAI remission (32%) than that in the MTX group (20%). At weeks 24 and 52, significantly higher proportions of patients in the TCZ8 + MTX group achieved ACR/EULAR indices of remission (29% and 36%, respectively) than those in the MTX group (16% and 22%, respectively). All three tocilizumab groups achieved a significant reduction in structural joint damage at week 52, as measured by VdH mtss, with the greatest reduction observed in the TCZ8 + MTX group. (Figure 2) Both the TCZ4 + MTX and TCZ8 + MTX groups achieved significantly greater improvements in physical function (as measured by change from baseline in HAQ-DI) compared with the MTX group after 24 weeks. This significant improvement in physical function over the MTX group remained true for the TCZ8 + MTX group at 52 weeks. (Figure 3) Safety The rates of adverse events (AEs), serious AEs, and AEs of special interest were similar between all treatment groups. The rates of liver transaminase elevations, from normal at baseline to the highest possible postbaseline value over 52 weeks, were highest in the groups who received tocilizumab + methotrexate. (Table 1) Figure 2. Secondary endpoint: structural joint damage (ITT population) Mean change from baseline in VdH mtss * 0.08 MTX (N = 267) TCZ8 + MTX (N = 273) TCZ8 monotherapy (N = 275) TCZ4 + MTX (N = 267) Week ITT = intent to treat; MTX = methotrexate; TCZ = tocilizumab; VdH mtss = van der Heijde modified Total Sharp Score *p <0.001 (vs. MTX). p <0.05 (vs. MTX), but tested after the hierarchical chain was broken. Figure 3. Secondary endpoint: physical function (ITT population) Time, weeks Change from baseline in HAQ-DI (mean ± SE) MTX (n = 246 [week 24]; 214 [week 52]) TCZ8 + MTX (n = 250 [week 24]; 228 [week 52]) TCZ8 monotherapy (n = 265 [week 24]; 230 [week 52]) TCZ4 + MTX (n = 255 [week 24]; 227 [week 52]) * * 1.2 HAQ-DI = health assessment questionnaire-disability index; ITT = intent to treat; MTX = methotrexate; SE = standard error; TCZ = tocilizumab *Comparison of TCZ8 + MTX vs. MTX, p <0.05. Comparison of TCZ4 + MTX vs. MTX, p <0.05 analyzed below the hierarchy break. New Evidence in Rheumatology March

29 Table 1. Shifts in liver transaminase levels from normal at baseline to highest postbaseline value over 52 weeks (safety population) Highest postbaseline value >ULN 3x ULN ALT AST >3x ULN 5x ULN ALT AST >5x ULN ALT AST Consecutive elevation >3x ULN* ALT AST MTX N = 282 n (%) 104 (36.9) 84 (29.8) 11 (3.9) 2 (0.7) 2 (0.7) 0 1 (0.4) 0 TCZ8 + MTX N = 290 n (%) 141 (48.6) 131 (45.2) 28 (9.7) 10 (3.4) 9 (3.1) 5 (1.7) 15 (5.2) 2 (0.7) TCZ8 monotherapy N = 292 n (%) 104 (35.6) 84 (28.8) 10 (3.4) 2 (0.7) 4 (1.4) 2 (0.7) 1 (0.3) 0 ALT = alanine aminotransferase; AST = aspartate aminotransferase; MTX = methotrexate; TCZ = tocilizumab; ULN = upper limit of normal * Elevations occurred on 2 consecutive study visits. ALT ULN = 55 U/L; AST ULN = 40 U/L. TCZ4 + MTX N = 289 n (%) 113 (39.1) 79 (27.3) 19 (6.6) 5 (1.7) 6 (2.1) 1 (0.3) 7 (2.4) 2 (0.7) Key conclusions Tocilizumab therapy was effective, in combination with methotrexate and as monotherapy, in methotrexate-naïve patients with early, active RA. All tocilizumab groups achieved greater inhibition of structural joint damage than those who received placebo + methotrexate. Optimal results were achieved for patients treated with tocilizumab 8 mg/kg + methotrexate, which showed superior results to placebo + methotrexate for the primary and key secondary endpoints. Overall, the safety profile observed in this population of methotrexate-naïve, early RA patients was consistent with the known safety profile of tocilizumab. Reference: 1. Burmester GR, Rigby W, van Vollenhoven RF, et al. Tocilizumab in combination therapy and monotherapy versus methotrexate in methotrexate-naïve patients with early rheumatoid arthritis: clinical and radiographic outcomes from a randomized, placebo-controlled trial. ACR Annual Meeting Abstracts 2013:2767. van Vollenhoven RF, et al. ACR 2013:2351 Tocilizumab in patients with rheumatoid arthritis and rates of malignancy: results from clinical trials Background Although patients with rheumatoid arthritis (RA) have an overall malignancy risk similar to that of the general population, they appear to be at increased risk for certain anatomic site-specific malignancies, including lymphoma, lung, and skin cancers. Chronic inflammation and the use of immunosuppressive therapies have been associated with increased risk for malignancy in patients with RA. Interleukin (IL)-6 has also been implicated in the carcinogenesis of various cancers. Tocilizumab is a monoclonal antibody that binds to IL-6 receptors and inhibits IL-6 signaling pathways. The efficacy and safety of tocilizumab for the treatment of RA have been demonstrated in phase III and IV randomized controlled trials. The objective of this study was to assess the risk for malignancy in patients with RA who were exposed to long-term tocilizumab treatment New Evidence in Rheumatology March 2014

30 In Supportive Care Oncology Study design Safety data from the following studies were included: Five phase III placebo-controlled studies: OPTION, TO- WARD, RADIATE, AMBITION, LITHE; Their long-term extension studies: GROWTH95, GROWTH96, LITHE extension phase; An open-label randomized clinical pharmacology study; Six-month data from the phase IV tocilizumab monotherapy study (ADACTA). The doses of tocilizumab in these studies were as follows: Phase III placebo-controlled studies: tocilizumab intravenous (iv) 8 mg/kg ± methotrexate/disease-modifying antirheumatic drug (DMARD), tocilizumab iv 4 mg/kg + methotrexate/dmard, or placebo/methotrexate/dmard every four weeks; Long term extension studies: open-label tocilizumab 4 or 8 mg/kg ± methotrexate/dmard every four weeks; Clinical pharmacology study: single dose of tocilizumab 10 mg/kg; ADACTA study: tocilizumab 8 mg/kg every four weeks. Data were assessed in two patient populations: Pooled placebo-controlled population: data from the five double-blind phase III trials; Tocilizumab all-exposed population: data from all patients who received one dose of tocilizumab from all studies examined. Malignancies were identified by the preferred terms contained in the Malignant or Unspecified Tumors Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQ) Narrow. Rates of malignancy adverse events (AEs) were calculated overall and by 6-month periods as the total number of AEs divided by the total patient year (pt-yrs) duration and were expressed per 100 pt-yrs with a 95% confidence interval (CI). The following malignancy rates were calculated: Overall malignancy rate: based on all reported events; Adjudicated malignancy rate: based on events identified by the MedDRA SMQ and adjudicated as malignant after medical review of event details by medically qualified clinical scientists employed by the study sponsor. The standardized incidence ratio (SIR) was used to compare the observed number of malignancies in the tocilizumab allexposed population with that expected if the tocilizumab all-exposed population had the same age- and sex-specific rates of a general population. The age- and sex-specific malignancy rates for the years from the Surveillance, Epidemiology, and End Results (SEER) Program of the U.S. National Cancer Institute were used for calculation of the expected number of site-specific malignancies in the tocilizumab all-exposed population. Key findings Patient characteristics The pooled placebo-controlled population consisted of 4,098 patients (2,644 treated with tocilizumab ± methotrexate/dmard and 1,454 treated with placebo, methotrexate, or DMARDs): The total pt-yrs duration was 1,560.3 pt-yrs for patients treated with tocilizumab; Baseline demographics and RA disease characteristics were well balanced between treatment arms within each study. The tocilizumab all-exposed population consisted of 4,171 patients: Mean duration of exposure to tocilizumab was 3.9 years, leading to a total observation time of 16,204.8 pt-yrs; Most patients were female (82%) and white (75%) with moderate-to-severe RA (median 28-joint disease activity score: 6.54), and included patients who had inadequate responses to DMARDs or tumour necrosis factor inhibitors, or who were methotrexate naïve. Overall malignancies In the pooled placebo-controlled population, the overall rate of events in tocilizumab-treated patients (1.60 [95% CI: ] per 100 pt-yrs) was comparable to the rate in placebo, methotrexate, or DMARD-treated patients (1.48 [95% CI: ] per 100 pt-yrs). There was no evidence for differences in patterns of type of malignancy reported between groups. The adjudicated malignancy rate was numerically higher in the placebo, methotrexate, or DMARD-treated patients (1.35 [95% CI: ]) compared with the tocilizumab-treated patients (1.09 [95% CI: ); however, the 95% CIs were overlapping, and the tocilizumab arm had almost twice the exposure because of the study desgins. Therefore, it cannot be concluded that there was a difference between the two treatment arms. In the tocilizumab all-exposed population, the overall rate of events was 1.54 (95% CI: ) per 100 pt-yrs. The most commonly reported adjudicated malignancies were nonmelamona skin cancers (NMSC). The adjudicated malignancy rate including NMSC was 1.26 (95% CI: ) events per 100 pt-yrs and remained constant over time. (Figure 1) The adjudicated malignancy rate excluding NMSC was 0.84 (95% CI: ) events per 100 pt-yrs. New Evidence in Rheumatology March

31 Figure 1. Adjudicated malignancy rate (including NMSC) over time in the tocilizumab all-exposed population 5 4 Malignancies/100 pt-yrs >66 Time (months) Months Exposure, pt-yrs Malignancies, n >66 1,877 1,679 1,551 1,477 1,410 1,356 1,316 1,269 1,226 1,139 1, Rate/100 pt-yrs (95% CI) 0.96 ( ) 1.1 ( ) 0.9 ( ) 1.4 ( ) 1.4 ( ) 1.1 ( ) 1.5 ( ) 1.6 ( ) 1.7 ( ) 0.97 ( ) 1.3 ( ) 1.4 ( ) CI = confidence interval; NMSC = nonmelanoma skin cancer; pt-yrs = patient-years *Data are presented as rates/100 pt-yrs, and error bars are 95% CIs. Standardized incidence ratios SIRs were calculated for overall malignancy and for specific anatomic sites based on the adjudicated malignancy rate excluding NMSC, as the SEER database does not collect data on NMSC. All SIRs >1 and having 95% CIs excluding 1.00 were statistically significant. The SIR for overall malignancy was 1.16 (95% CI: ), indicating that the observed number of overall malignancies in tocilizumab-treated patients was not statistically different from that expected based on age- and sex-specific rates in the reference U.S. general population. (Figure 2) SIRs for specific anatomical sites were based on small numbers of cases and were not statistically significant, except for two malignancy types with SIRs >1: lung or bronchus (SIR 2.19 [95% CI: ]) and cervix uteri (SIR 3.51 [95% CI: ]): Of the 29 adjudicated reports of lung and bronchus cancer, 83% occurred in patients with a history of smoking; All five cases of cervical cancer occurred in patients from regions with disproportionately high burdens of cervical cancer and lack of national cervical cancer screening. 30 New Evidence in Rheumatology March 2014

32 In Supportive Care Oncology Figure 2. Standardized incidence ratios for malignancy (tocilizumab all-exposed population) No. of observations SIR (95% CI) No. of observations SIR (95% CI) All sites 136* 1.16 ( ) Urinary bladder ( ) Lung or bronchus ( ) Melanoma of the skin ( ) Female breast ( ) Oral cavity and pharynx ( ) Prostate ( ) Rectum ( ) Colon, excluding rectum ( ) Thyroid ( ) Corpus uteri ( ) Esophagus ( ) Cervix uteri ( ) Brain ( ) Non-Hodgkin lymphoma ( ) Leukemia ( ) Stomach ( ) Pancreas ( ) Ovary ( ) Kidney or renal pelvis ( ) SIR (95% CI) SIR (95% CI) *Includes 13 malignant cases (anal cancer, bone and joint, larynx, skin [excluding basal and squamous], soft tissue [including heart], other endocrine and thymus, and other) that are not listed in an anatomic site category. Includes one malignant case of nasopharynx, two malignant cases of tongue, and one pharyngeal cancer. Key conclusions The overall risk for malignancy in patients treated with tocilizumab was not statistically different from that in the U.S. general population. The patterns of malignancy observed are consistent with those expected in the RA population. The SEER database used for SIR analysis limits comparisons to the U.S. general population and excludes malignancies not collected, including NMSC, the most commonly reported malignancy in patients treated with tocilizumab. The data should be interpreted with this in mind. Furthermore, it should be noted that SIRs for specific types of malignancies were based on small numbers of cases; therefore, these SIR estimates could be unstable. Reference: 1. van Vollenhoven RF, Rubbert-Roth A, Sebba A, et al. Tocilizumab in patients with rheumatoid arthritis and rates of malignancy: results from clinical trials. ACR Annual Meeting Abstracts 2013:2351. New Evidence in Rheumatology March

33 Canadian Perspective by Dr. Janet Pope At the American College of Rheumatology 2013 Annual Meeting, investigators presented studies on a new route of administration for the interleukin-6 receptor antibody, tocilizumab, in the treatment of rheumatoid arthritis (RA), as well as comparisons between tocilizumab and other biologics with respect to efficacy and cardiovascular disease (CVD) risk. The SUMMACTA study, presented by Burmester et al., compared the efficacy and safety of subcutaneous (sc) tocilizumab with those of intravenous (iv) tocilizumab, as each was used in combination with traditional disease-modifying antirheumatic drugs (DMARDs) over 49 weeks in the treatment of patients with active RA. The main finding of this randomized, controlled trial (as well as the BREVACTA study, which used the same protocol but with a different dose of tocilizumab) was that tocilizumab sc was just as efficacious as tocilizumab iv. Consequently, the advantage of a sc injection is that it takes less time than an iv infusion and may be preferred by many patients who do not wish to attend monthly infusions or receive regular iv injections. Tocilizumab sc seems to be a good option for patients initiating tocilizumab and could allow patients to switch from iv to sc. Additionally, more patients continued with tocilizumab sc compared with those who received tocilizumab iv after the double-blind period in this study, so the sc formulation will likely have a greater role to play in the near future for RA patients who are prescribed tocilizumab. As with the efficacy data, safety profiles were similar between the two types of tocilizumab delivery, again reassuring us that tocilizumab sc is a viable option. Immunogenicity was not a problem in either group; development of antitocilizumab antibodies was very uncommon in both groups (approximately 1%). There is always the fear that if the route of administration is changed then there may be a change in antibody development, but anti-drug antibodies were very low in the iv and sc groups. The SUMMMACTA and BREVACTA studies can be taken together as demonstrating tocilizumab sc to be noninferior and clinically equal to tocilizumab iv. From these data, we can conclude that tocilizumab sc is an alternative to tocilizumab iv. Once tocilizumab sc is approved in Canada, I will initiate most patients on it and offer iv patients the sc alternative. I believe crossing over from tocilizumab iv to tocilizumab sc will be a welcome change for many patients, and they should receive similar benefit with no new safety signals. Gabay et al. presented a subset of the ADACTA trial a randomized, controlled trial that showed that the efficacy of tocilizumab monotherapy was superior to that of adalimumab monotherapy in active RA. 1 In general, the use of methotrexate with a biologic increases efficacy and durability of treatment in patients with RA. However, this may not be the case with tocilizumab; the ACT-RAY study showed that the efficacy of tocilizumab monotherapy was not statistically different from that of tocilizumab in combination with methotrexate. 2 The durability of tocilizumab monotherapy was not assessed in the ACT-RAY study. Not every patient can use a background DMARD; as in other registries around the world, Canadian data suggests that one third of RA patients using biologics are on monotherapy. Therefore, tocilizumab is a viable option in these patients and may be the preferred biologic choice over time. In this sub-study of ADACTA, high-density lipoprotein (HDL) composition was measured in enrolled patients with very active RA; this sample is representative of a subset of Canadian patients. The results showed that some of the good subunits of HDL (i.e., those that confer a healthy phenotype) improved when disease activity decreased in the patients studied, resulting in an improved lipid profile. Increases in low-density lipoprotein (LDL) and HDL at week 8 occurred in both groups, but were more often seen with adalimumab despite the use of maximum doses of tocilizumab. However, no changes were observed in the apob/apoa1 ratio in either group. Reductions in HDL-SAA and spla 2 were observed in both treatment groups, but a greater reduction was observed with tocilizumab. These results show that treatment of inflammation with tumour necrosis factor inhibitors (TNF-Is) can increase lipids; however, the lipid increases were not relevant with respect to a need for treatment with lipid-lowering drugs in this study, and the lipid profile, on average, favoured less risk of atherosclerosis. We are becoming more aware that a patient s lipid profile extends beyond the level of lipids to include an examination of lipoprotein type, as well as the expression patterns of specific subunits in these lipoproteins. This study has shown that when we use a biologic and control disease activity, we see a better lipid profile in our patients despite also seeing a rise in total cholesterol, resulting in reduced CVD risk. The presence of dyslipidemia would not affect the choice of treatment for a patient with RA in our clinic; it would just remind us to treat the patient for dyslipidemia if the lipid profile met guidelines for cholesterol-lowering therapy. In Canada, CVD risk assessment is probably not done as thoroughly as it should be in patients with RA. We do know that patients with RA have an elevated risk for CVD, but it is likely that many rheumatologists do not routinely test lipids in their patients. It is now easier to test lipids since fasting is no longer required, making the test easier for physicians to order and for patients to complete. The product monograph for tocilizumab does remind us to test lipids after month 2. In our clinic, we usually test lipids at month 3 because we can judge the efficacy of tocilizumab in the patient at that time and test lipids if the drug 32 New Evidence in Rheumatology March 2013

34 In Supportive Care Oncology is to be continued. Lipids should be tested at some point, as a small percentage of patients will need lipid-lowering medication (according to local or national guidelines). However, I think we generally forget to test lipids when patients with RA are using other drugs. We also generally forget to monitor other CVD risk factors, such as smoking, blood pressure, and blood sugar levels. As well, we need to inform the patients primary care physicians that RA can be an increased risk for CVD in patients with severe RA family physicians might not have this knowledge. Buckley et al. presented a network meta-analysis of the efficacy of various DMARDs with and without methotrexate in patients with RA. It is important to understand that a network meta-analysis attempts to compare studies of different drugs. We know that there will never be a randomized, controlled trial comparing all potential biologics, as the sample size required would not be feasible. A network meta-analysis is one way to provide a relative ranking of these drugs by using statistical methods to subtract the placebo and adjust for confounding variables within each trial. It is difficult to compare between trials because of heterogeneity in trial design (e.g., differences in inclusion/exclusion criteria, background treatments, or duration of treatment); therefore, it is also difficult to understand and interpret the conclusions. Each person must decide if the meta-analysis has been performed well enough to account for these inter-study differences. In this study, the authors concluded that tocilizumab monotherapy provided a greater response than those of TNF-Is and tofacitinib in patients with RA. Also, the response to tocilizumab monotherapy was similar to that of tocilizumab plus methotrexate. While these findings are true, we do not have many head-to-head comparisons between tocilizumab and other drugs (apart from the ADACTA trial 1 ), so the data are composed mostly of inter-study comparisons. While the meta-analysis is valid, we do not know all of the confounding variables, and the conclusions must be interpreted with caution. The data from this study are very interesting, and one may consider tocilizumab monotherapy as a biological drug of choice if monotherapy is necessary. However, a limitation of the study is that the reasons for these patients to be on monotherapy are unknown. While the presence of comorbidities, lack of efficacy, or intolerabilities may be factors in this decision, it may also be the case that patients switched to monotherapy because they were doing very well on the biologic in combination with a DMARD. This analysis did not look at these factors, which would influence our treatment decisions. Additionally, the long-term durability of tocilizumab and tofacitinib monotherapy has not been studied (i.e., in the long term, we do not know if the durability of tocilizumab is altered by background methotrexate). At our clinic, we try to give all biologics as combination therapy if possible because we have seen improved durability with the addition of a DMARD, even at a low dose. However, we will get more data about the durability of these monotherapies over time, which may change or confirm my opinion. References: 1. Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab monotherapy versus adalimumab montherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 2013;381: Dougados M, Kissel K, Sheeran T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis 2013;72: New Evidence in Rheumatology March

35 Investigator Commentary An Interview with Dr. Gerd Burmester on the SUMMACTA Trial, Comparing Two Methods of Tocilizumab Delivery At the ACR 2013 Annual Meeting, New Evidence spoke with Dr. Gerd Burmester about the results of the SUMMACTA trial, which compared the intravenous and subcutaneous formulations of tocilizumab in the treatment of rheumatoid arthritis. New Evidence: What is the SUMMACTA clinical trial? Dr. Burmester: The SUMMACTA trial compared the intravenous (iv) and subcutaneous (sc) formulations of tocilizumab in patients with rheumatoid arthritis. The purpose of the study was to determine if the efficacy and safety of tocilizumab iv and sc were comparable and to investigate the pharmacokinetics of these compounds. New Evidence: What was the rationale for this study? Dr. Burmester: In Germany, most patients prefer to receive tocilizumab sc because it can be given at home with no hospital visits required. This gives the patients considerable freedom. In addition, the logistics of giving tocilizumab iv can be difficult, especially if the schedule needs to be changed. In the long run, if trials show that tocilizumab sc is comparable to its iv formulation, it will be much easier for physicians to give tocilizumab. New Evidence: Patients were initially randomized to receive tocilizumab sc or iv during the double-blind phase of this trial, and then re-randomized during the open-label extension phase. Please comment on the strengths and weaknesses of this crossover design. Dr. Burmester: Patients either stayed on their original mode of tocilizumab delivery or switched to the opposite mode. Some sc patients were switched to iv and some iv patients were switched to sc. This is very important because both of these scenarios could occur in clinical practice, and we need to know if switching will give patients the same efficacy and safety as their original mode of delivery with this drug. New Evidence: Were there any significant differences between the sc and iv groups at the time of crossover (i.e., at the initiation of the long-term extension)? Dr. Burmester: No, there were no differences between the groups at the time of crossover. 34 New Evidence in Rheumatology March 2014

36 New Evidence: The efficacy of tocilizumab was found to be similar between the sc and iv groups. Based on this, would you recommend one mode of delivery over another, and why or why not? Dr. Burmester: I prefer the sc formulation of tocilizumab because of its ease of use. Also, in Germany we often run out of infusion spaces because so many drugs are administered intravenously. Using tocilizumab sc frees up some of these spaces. New Evidence: The safety of tocilizumab was found to be similar between the sc and iv groups, with the exception of a higher rate of injection site reactions (ISRs) in the sc group that was lower at 49 weeks than at 24 weeks of treatment. Do you feel this difference in adverse events (AEs) would prevent you from using tocilizumab sc? Why or why not? Dr. Burmester: The increased rate of ISRs would not prevent me from using tocilizumab sc because while patients noticed the reactions, they did not discontinue the drug because of them. The efficacy and ease of use of tocilizumab sc outweighs this minor side effect. New Evidence: Was there an increase in anti-tocilizumab antibody formation with the sc formulation? How does antibody formation correlate with AEs or loss of efficacy? Dr. Burmester: Interestingly, there was no increase in anti-tocilizumab antibody formation with the sc mode of delivery. This is surprising because the sc delivery is usually more immunogenic; however, we did not see a difference between tocilizumab sc and iv. This is reassuring. If we had observed an increase it could have prevented the use of tocilizumab sc, but that was not the case. New Evidence: Do you think there are any barriers to prevent the use of tocilizumab sc? Dr. Burmester: No. If one decides to use tocilizumab, I would personally always go with the sc formulation, unless the patient is very non-compliant or has a fear of self-injection. Even in this latter case, the patient can go to a clinic and have a nurse perform the injection, so these occurrences are very rare. New Evidence: Will the results of this study influence your decision to use tocilizumab sc over iv, or vice versa? Dr. Burmester: Yes, I will use the sc form of tocilizumab. New Evidence: Would you feel comfortable switching patients who are stable on tocilizumab iv to the sc formulation, or vice versa? Dr. Burmester: Yes. I would offer these possibilities to patients, but ultimately it is up to the patient to decide which version of tocilizumab they would like to receive. New Evidence in Rheumatology March

37 Rituximab in Rheumatoid Arthritis Treatment Rituximab: long-term safety, efficacy, and treatment strategies Rheumatoid arthritis (RA) is linked with high risk of serious infections, lymphomas, and cardiovascular disease deaths. 1 4 The risks of infection and malignancy events may be increased by the use of biological therapies, including tumor necrosis factor inhibitors (TNF-I); therefore, follow-up of patients while on therapy is very important to evaluate long-term safety. 1,5 8 Biologics such as abatacept, tocilizumab, and rituximab are used after TNF-I failure in patients with RA; however, the order of use of biologic agents still remains debatable and is the subject of clinical research. Rituximab is a chimeric monoclonal antibody that selectively targets CD20-positive B cells. 9,10 In combination with methotrexate, rituximab is approved for the treatment of patients with moderate-to-severe RA with inadequate response or intolerance to TNF-Is. Sustained control of disease activity can be attained by multiple treatment courses, but optimal dose and retreatment schedule are still not clear. 11 Research has shown that rituximab has a good safety profile, with most studies showing rates of serious adverse events and infections with rituximab that were similar to those with placebo. 11 Moreover, rituximab was shown to be well tolerated over time and multiple courses. 12 While these results are promising, long-term safety for rituximab in patients with RA still remains to be established, particularly regarding the risks of infections and malignancies. At the American College of Rheumatology (ACR) 2013 Annual Meeting, studies were presented that addressed the long-term safety of rituximab in patients with RA, the safety of administering rituximab at a more rapid infusion rate, the use of rituximab as a second-line agent after failure to an initial TNF-I, as well as retreatment strategies with rituximab and effectiveness of repeated courses of rituximab. This section reports on five presentations delivered at ACR 2013: An analysis of long-term safety of rituximab in patients with moderate-to-severe, active RA in the global clinical trial program covered data from 3,595 patients with up to 11 years followup, showing rituximab tolerability over time and with multiple courses. Aside from infusion-related reactions (IRRs) and low immunoglobulin levels (where there was a lack of placebo comparator), the overall safety profile of rituximab was similar to that of the pooled placebo population and consistent with previous analyses. Use of rituximab as a second-line biologic agent compared with adalimumab, etanercept, and infliximab was evaluated in patients with RA using the RHUMADATA clinical database and registry. Results showed that rituximab had a better 5-year retention rate than the comparator agents. The RATE-RA study evaluated the safety of administering the second infusion of a rituximab course and following infusions at a more rapid rate of two hours in patients with RA. The incidence of IRRs with the faster second infusion was similar to the weighted historical rate, and the incidence of IRRs for subsequent infusions was also low. A study compared two retreatment strategies: fixed vs. on-flare retreatment with rituximab in RA patients. Using pooled data from the Collaborating European Registries for Rituximab in RA (CERERRA) project, results showed that a fixed retreatment strategy was more effective. The effectiveness of repeated courses of rituximab in patients with RA was evaluated using pooled data from the CERERRA project. Additional clinical improvement was observed with repeated retreatment after the first course of rituximab. 36 New Evidence in Rheumatology March 2014

38 In Supportive Care Oncology References: 1. van Vollenhoven RF, Emery P, Bingham III CO, et al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis 2013;72: Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006;295: Baecklund E, Iliadou A, Askling J, et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum 2006;54: Wolfe F, Michaud K. Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy. Am J Med 2004;116: Maini RN, Breedveld FC, Kalden JR, et al. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum 2004;50: Genovese MC, Bathon JM, Fleischmann RM, et al. Longterm safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumatol 2005;32: Schiff MH, Burmester GR, Kent JM, et al. Safety analyses of adalimumab (HUMIRA ) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis 2006;65: Askling J, Dixon W. The safety of anti-tumour necrosis factor therapy in rheumatoid arthritis. Curr Opin Rheumatol 2008;20: Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350: Buch MH, Smolen JS, Betteridge N, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2011;70: Leandro MJ, Becerra-Fernandez E. B-cell therapies in established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2011;25: van Vollenhoven RF, Emery P, Bingham III CO, et al. Long term safety of patients receiving rituximab in rheumatoid arthritis clinical trials. J Rheumatol 2010;37: van Vollenhoven RF, et al. ACR 2013:2342 Long-term safety of rituximab: pooled analysis of the rheumatoid arthritis global clinical trial program over 11 years Background At ACR 2013, van Vollenhoven and colleagues conducted an updated overall safety analysis of rituximab in patients with rheumatoid arthritis (RA) in the global clinical trial program. 1 Study design This study was a pooled observational case analysis of safety data of patients with moderate-to-severe, active RA treated with rituximab plus methotrexate in a global clinical trial program (eight randomized clinical trials, two long-term open-label extensions, and one open-label prospective study). Each rituximab course consisted of either two x 1,000 mg or two x 500 mg intravenous infusions, two weeks apart. Prior to each rituximab infusion, all patients received 100 mg methylprednisolone iv; most patients also received acetaminophen and an antihistamine. Rituximab repeat treatment was based on physician decision of clinical need and included evidence of active disease (either swollen/tender joint counts 8 or 28-joint disease activity score 2.6). All patients received concomitant methotrexate 10 to 25 mg/week at a stable dose. Background oral corticosteroids and nonsteroidal anti-inflammatory drugs were also permitted. The analysis consisted of the following populations: Rituximab all-exposure population (all patients exposed to at least one or part of one rituximab infusion, regardless of dose); Rituximab long-term population (a subset of the all-exposure population with >5 years follow-up from first rituximab exposure); Pooled placebo population (all patients who received placebo during placebo-controlled and study follow-up periods). Key findings Patient exposure and demographics As of September 2012, 3,595 patients had received up to 20 courses of rituximab over a period of 11 years. The number of patients available for analysis was: Rituximab all-exposure population: 3,595 (14,816 patient-years [pt-yrs]); Rituximab long-term population: 1,246 (8,970 pt-yrs); Pooled placebo population: 818 (1,107 pt-yrs). The pooled placebo population included patients with a substantially shorter mean duration of follow-up compared with those of the rituximab populations (>50% withdrew from placebo followup by one year and 93% by three years). Differences in patient numbers and duration of follow-up should be considered during interpretation of data. New Evidence in Rheumatology March

39 Patients with follow-up of >5 years had a longer mean RA disease duration and a greater number (n = 2.3) of previous disease-modifying antirheumatic drugs (excluding methotrexate) than the all-exposure and placebo populations. Baseline demographics and disease characteristics were otherwise similar across the groups. Overall adverse events Rates of adverse events (AEs) and serious adverse events (SAEs) were similar in the all-exposure, long-term, and placebo populations. (Table 1) The rate of all AEs over time was highest during the first six months after the first rituximab exposure, in part due to infusion-related reactions (IRRs), which predominantly occurred with the first infusion of the first course. (Figure 1) The rates of AEs and SAEs subsequently decreased and remained stable thereafter, irrespective of the number of courses received. (Figure 2) SAEs that occurred in >1% of rituximab patients were exacerbations of RA (n = 83 [2%]), pneumonia (n = 74 [2%]), osteoarthritis (n = 55 [2%]), and falls (n = 62 [2%]). Infections Overall rates of all infections and serious infectious events (SIEs) were similar across the analysis populations. (Table 1) The rate of SIEs generally remained stable over time and over multiple treatment courses. (Figure 3) A numerically higher SIE rate between years five and six was not observed in subsequent years. Larger CIs were observed at >9 years due to low pt-yrs exposure. The most frequent SIEs in the all-exposure population were lower respiratory tract infections, predominantly pneumonia (2%). Serious opportunistic infections were rare (all-exposure: 0.05 events/100 pt-yrs; placebo: 0.09 events/100 pt-yrs). Table 1. Summary of adverse event rates per 100 patient-years Rituximab all-exposure (n = 3,595) Rituximab long-term ( >5 years) (n = 1,246) Pooled placebo (n = 818) Exposure (pt-yrs) 14,816 8,970 1,107 AE rate (95% CI) ( ) ( ) ( ) SAE rate (95% CI) ( ) ( ) ( ) Infection rate (95% CI) ( ) ( ) ( ) SIE rate (95% CI) 3.76 ( ) 2.71 ( ) 3.79 ( ) AE = adverse event; CI = confidence interval; pt-yrs = patient-years; SAE = serious adverse event; SIE = serious infectious event Figure 1. Incidence of IRRs by treatment course (all-exposure population) Patients with any IRR (%) First infusion Second infusion Course 1 Course 2 Course 3 Course 4 Course 5 Course 6 Course 7 Course 8 Course 9 Course 10 First infusion: n = 3,595 2,750 1,744 1,471 1, Second infusion: n = 3,523 2,689 1,718 1,449 1, IRRs = infusion-related reactions 38 New Evidence in Rheumatology March 2014

40 In Supportive Care Oncology Figure 2. Rates of AEs over time: one-year increments (all-exposure population) 500 Rate of events/100 pt-yrs Annual rate of AEs Annual rate of SAEs 0 Total pt-yrs exposure 0 1 >1 2 >2 3 >3 4 >4 5 >5 6 >6 7 >7 8 >8 9 >9 10 > ,496 3,086 2,284 1,799 1,409 1, Time (years) AEs = adverse events; pt-yrs = patient-years; SAEs = serious adverse events Figure 3. Rate of SIEs* over time in one-year increments (all-exposure population) Overall SIE rate = 3.76/100 pt-yrs SIEs/100 pt-yrs Total pt-yrs exposure 0 1 >1 2 >2 3 >3 4 >4 5 >5 6 >6 7 >7 8 >8 9 >9 10 > ,496 3,086 2,284 1,799 1,409 1, Time (years) *Serious and/or those requiring intravenous antibiotics. Error bars represent 95% CIs of the SIE rate (/100 pt-yrs). Rate calculation for all-exposure population includes up to 11 years of follow-up. CIs = confidence intervals; pt-yrs = patient-years; SIEs = serious infectious events Seven events previously reported in the all-exposure population include two cases of atypical pneumonia (no organisms isolated), Candida septicemia, pharyngeal abscess (organism unspecified), Scedosporium lung infection, Pneumocystis jirovecii pneumonia, and progressive multifocal leukoencephalopathy with fatal outcome; one event occurred in the placebo population (P. jirovecii pneumonia). There were no cases of hepatitis B reactivation and one case of de novo hepatitis B infection in the all-exposure population. Two cases of pulmonary tuberculosis (TB), both treated with anti-tb medication, occurred in the all-exposure population. No cases of extrapulmonary TB, atypical mycobacterial infection, or multi-drug resistant TB were reported. New Evidence in Rheumatology March

41 The use of subsequent biologics, including tumor necrosis factor (TNF) inhibitors, was not associated with an increased SIE rate. (Table 2) SIE rates were similar (3.65 events/100 pt-yrs [95% CI: ] vs [95% CI: ]) in patients who received their biologic < 6 months (n = 98) and 6 months (n = 255), respectively, after last rituximab dose. In the subgroup of patients (n= 224) with CD19+ cell counts <20 cells/µl prior to their subsequent biologic, the SIE rate after the biologic was 5.03 events/100 pt-yrs (95% CI: ). Table 2. SIEs rates before and after treatment with biologics and TNF-Is Total exposure (pt-yrs) Immunoglobulins Following rituximab treatment, low immunoglobulin (Ig) concentrations (particularly IgM, less often IgG) were observed. For both Ig classes, SIE rates per 100 pt-yrs were similar before (IgM, 2.80 [95% CI: ]; IgG, 6.75 [95% CI: ]) and during/after development of low Ig (IgM, 3.84 [95% CI: ]; IgG, 8.16 [95% CI: ]). SIE rates in patients who developed low IgG levels were higher than corresponding rates in patients who never developed low IgG and the all-exposure population, both before and after development of low IgG levels. This suggests that these patients may have a higher inherent risk of developing SIEs. Limitations included low patient numbers in the IgG subgroup (n = 143), lack of a placebo comparator, and lack of correlation between SIE onset and recording of low Ig levels. Cardiac events All patients receiving any biologic following rituximab (n = 353) Before other biologic After other biologic Subset of patients receiving a TNF-I following rituximab (n = 280) Before TNF-I After TNF-I SIEs, n SIEs/ 100 pt-yrs (95%CI) 4.40 ( ) 4.07 ( ) 4.28 ( ) CI = confidence interval; pt-yrs = patient-years; SIEs = serious infectious events; TNF-I = tumour necrosis factor inhibitor 3.61 ( ) Myocardial infarction (MI) was the most frequent cardiac AE (56 events in 46 patients); most affected patients had 1 risk factor for MI. The rate of MI (0.39 events/100 pt-yrs) was consistent with rates in the general RA population ( events/100 pt-yrs). Malignancies In the rituximab all-exposure population, there were 109 confirmed serious malignancies, excluding nonmelanoma skin cancers and nonmalignant events (as identified by Sponsor medical review), providing a rate of 0.74 events/100 pt-yrs. There was no evidence of an increased risk of malignancy over time or rituximab course. The rate of confirmed malignancies (excluding nonmelanoma skin cancers) was similar to rates in the general RA population. (Table 3) For solid tumors, the most frequently reported malignancy was breast cancer (16 events). Age- and sex-matched standardized incidence ratios for all confirmed malignancies and for breast cancer did not indicate an increased risk of malignancy for rituximab-treated patients with RA compared with the general U.S. population (SEER database) and with published data in adults with RA. (Table 3) Table 3. Rates and standardized incidence ratios of malignancy in the all-exposure population and from published data in adults with RA Rituximab (all-exposure population) (95% CI) RA observational studies Danish Cancer Registry National Databank for Rheumatic Diseases Malignancy incidence in rituximab-treated RA All-exposure population (95% CI) Meta-analysis of malignancy incidence in adult patients with RA (95% CI) Rate (per 100 pt-yrs) Any site* Breast 0.74 ( ) 0.14 ( ) Standardized incidence ratio Any site* Breast 1.07 ( ) 0.63 ( ) 1.05 ( ) 0.84 ( ) *Excluding nonmelanoma skin cancer and nonmalignant events. Only female patients. Surveillance Epidemiology and End Results database was used to obtain age- and sexspecific incidence ratio of malignancies for the U.S. general population for standardized incidence ratio calculations. CI = confidence interval; pt-yrs = patient-years; RA= rheumatoid arthritis 40 New Evidence in Rheumatology March 2014

42 In Supportive Care Oncology Key conclusions These long-term data from 3,595 patients with up to 11 years of follow-up (14,816 pt-yrs) confirm that rituximab remains well tolerated over time and multiple courses, with a consistent safety profile. No new safety signals were observed with increasing duration of exposure. IRRs predominantly occurred during the first infusion of the first course and were rarely serious. Serious and non-serious infection rates were similar to those in previous analyses and did not increase over time or course. The use of subsequent biologics, including TNF inhibitors, in patients with RA previously treated with rituximab was not associated with an increased SIE rate. Rates of MI and malignancies were consistent with those observed in epidemiologic data from other RA cohorts. Apart from IRRs and low Ig concentrations, the overall safety profile of rituximab remains similar to that of the pooled placebo population and is consistent with published data for moderate-to-severe RA and with previous analyses of this patient cohort. Reference: 1. van Vollenhoven RF, Emery P, Bingham III CO, et al. Long-term safety of rituximab: pooled analysis of the rheumatoid arthritis global clinical trial program over 11 years. ACR Annual Meeting Abstracts 2013:2342. Bessette L, et al. ACR 2013:432 Use of rituximab as second-line biologic agent compared with adalimumab, etanercept, and infliximab in patients with rheumatoid arthritis a report from the RHUMADATA clinical database and registry Background The order of use of biologic agents after failing a tumor necrosis factor inhibitor (TNF-I) is still a question for debate. Phase III trial data in patients with incomplete response to anti-tnf agents (TNF-IR) show comparable efficacy results across biologic agents and limited head-to-head studies have been published. Prospective registries offer a unique opportunity to observe the effectiveness (combined evaluation of efficacy and safety profile over time) of these agents in a clinical setting. At ACR 2013, Bessette and colleagues evaluated if patients with rheumatoid arthritis (RA) treated with rituximab after failing first anti-tnf agents have a different drug retention rate than patients similarly prescribed adalimumab, etanercept, or infliximab. 1 Study design Data were extracted from RA patients with TNF-IR who were prescribed adalimumab, etanercept, infliximab, or rituximab as a second biologic agent on or after January 1st, Baseline characteristics included age, disease duration, gender, health assessment questionnaire score, morning stiffness, fatigue and pain visual analog scale evaluations, C-reactive protein, erythrocyte sedimentation rate (ESR), rheumatoid factor, anticyclic citrullinated peptide antibody, tender joint count, swollen joint count, 28-joint disease activity score (DAS28), and clinical disease activity index. Five-year drug retention rates were estimated and compared using Kaplan-Meier survival estimates. Statistical analysis was performed using SAS version 9.3. RHUMADATA is a clinical database and registry used in daily clinical practice at the Institut de Rhumatologie de Montreal and Centre d Osteoporose et de Rhumatologie de Quebec. Key findings The data from 127 patients were extracted. No significant clinical differences in baseline variables were observed between treatment groups. (Table 1) The five-year retention rates of adalimumab, etanercept, infliximab, and rituximab after failing second-line anti-tnf agent were 28%, 27%, 13%, and 66%, with significant statistical differences (Logrank p <0.001). (Figure 1) New Evidence in Rheumatology March

43 Table 1. Baseline characteristics Second biologic agent Adalimumab Etanercept Infliximab Rituximab p All N Mean age (years) 56.1 (14.9) 62.3 (14.5) 47.8 (19.7) 62.4 (9.0) < (14.9) Disease duration (years) 3.9 (1.6) 3.1 (1.9) 4.4 (1.4) 3.3 (1.8) < (1.7) Female (%) ns 80.2 HAQ score 1.2 (0.7) 1.3 (0.6) 1.5 (0.8) 1.4 (0.5) ns 1.3 (0.7) Morning stiffness (min) 65.3 (131.7) 71.8 (169.8) 27.8 (26.8) (338.8) ns 83.4 (210.7) Fatigue (VAS) 5.1 (3.7) 4.2 (3.2) 4.6 (3.4) 5.3 (3.1) ns 0.7 (0.0) Pain (VAS) 5.2 (3.5) 4.7 (3.5) 4.0 (3.2) 5.5 (3.3) ns (0.0) CRP (mg/l) 16.8 (28.2) 13.1 (35.1) 22.9 (37.8) 15.8 (14.0) ns 3.4 (0.0) ESR (mm/hour) 26.9 (19.2) 22.3 (21.3) 30.8 (30.2) 33.7 (31.0) ns 3.4 (0.0) Rheumatoid factor (%) NA Negative Positive Anti-CCP (%) <0.03 NA Negative Positive TJC 5.4 (6.3) 5.8 (5.7) 9.5 (8.3) 6.2 (6.9) ns 6.1 (6.5) SJC 6.6 (5.3) 6.7 (5.3) 8.8 (8.2) 7.9 (6.0) ns 7.1 (5.7) DAS28(ESR) 3.7 (1.1) 3.4 (1.3) 4.5 (1.7) 4.3 (1.4) ns 3.9 (1.4) CDAI 20.0 (12.7) 20.2 (13.4) 28.3 (19.5) 22.5 (14.0) ns 21.5 (13.9) CCP = cyclic citrullinated peptide; CDAI = clinical disease activity index; CRP = C-reactive protein; DAS = disease activity score; ESR = erythrocyte sedimentation rate; HAQ = health assessment questionnaire; NA = not available; ns = not significant; SJC = swollen joint count; TJC = tender joint count; VAS = visual analog scale ns Figure 1. Survival probability = censored Log-rank p = Survival probability ,000 1,500 2,000 2, Drug failure or censoring time (days) Treatment groups 1. Adalimumab 2. Etanercept 3. Infliximab 4. Rituximab 42 New Evidence in Rheumatology March 2014

44 In Supportive Care Oncology Key conclusions As a second-line agent, in TNF-IR patients, rituximab demonstrates a better five-year retention rate than the comparator agents. It is to be noted that the usual limitations associated with observational studies (the non-randomized nature of the data and the potential for selection bias and confounding) apply to the present analysis. Reference: 1. Bessette L, Choquette D, Sauvageau D, et al. Use of rituximab as second line biologic agent compared with adalimumab, etanercept and infliximab in patients with rheumatoid arthritis. A report from the RHUMADATA clinical database and registry. ACR Annual Meeting Abstracts 2013:432. Pritchard CH, et al. ACR 2013:877 Results from the RATE-RA study: a multicentre, single-arm study to evaluate the safety of administering rituximab at a more rapid infusion rate in patients with rheumatoid arthritis Background The FDA-approved dose of rituximab in rheumatoid arthritis (RA) is two 1,000-mg intravenous (iv) infusions administered two weeks apart (one course), with recommended times of 4.25 hours and 3.25 hours for infusions 1 and 2, respectively. At ACR 2013, Pritchard and colleagues assessed the safety of administering the second infusion of a rituximab course and subsequent infusions at a more rapid rate of 2 hours. 1 Study design This was a multicentre, single-arm, open-label study. Historical data were used as an external control. Integrated data from phase II/III studies and their open-label extension studies in the rituximab clinical development program in RA as of September 2012 (N = 3,595 patients). The study was sized around n = 300 so that an increase by >3 4% in the infusion-related reaction (IRR) rate would be different with statistical significance from the reference rate. With no serious IRRs (SIRRs) for n = 300, there will be 95% confidence that the SIRR rate is <1.0%. Select inclusion criteria were: Adult RA patients with inadequate response to an anti-tumor necrosis factor (TNF) agent; Rituximab-experienced and -naïve patients; No more than two prior courses of rituximab. Most recent prior course of rituximab must be within 6 9 months. Receiving concomitant methotrexate; Selected safety criteria: No prior SIRR to any RA biologic; No grade 3/4 New York Heart Association congestive heart failure; No history of significant arrhythmia; Hypertension must be well controlled. All patients received the first rituximab infusion (infusion 1) on day 1 over 4.25 hours, the standard rate. The second rituximab infusion (infusion 2) on day 15 was over two hours (infusion 1 and 2 = course 1), as were both infusions 3 and 4 (course 2) six months later. Patients were premedicated with iv methylprednisolone, antihistamines, and analgesics prior to all rituximab infusions. The study objectives were as follows: Primary objective: to assess the safety of administering the second infusion (day 15) of a course of rituximab over a period of two hours. Secondary objective: to assess the safety of administering the first infusion of a second course (day 168) of rituximab over a period of two hours. New Evidence in Rheumatology March

45 Study design 351 atnf-ir patients enrolled (July 26, 2011 to June 8, 2012) Rituximab-naïve (n = 306 [87%]) Experienced (n = 45 [13%]) Primary end point: 24 hours post infusion 2 End of study: 4 weeks post infusion 4 No efficacy assessments Day 1 Day 15 Day 168 Day 182 Infusion 1: 1g, 4.25 hours Infusion 2: 1g, 2 hours Infusion 3: 1g, 2 hours Infusion 4: 1g, 2 hours atnf-ir = anti-tumour necrosis factor-inadequate response Key findings The enrolled patients (N = 351) had the following characteristics: Rituximab-naïve: n = 306 (87.2%); Rituximab-experienced: n = 45, of which 24 (6.8%) and 21 (6.0%) had received one or two prior rituximab courses, respectively; Mean age: 55.5 (SD = 11.5) years, with 19.7% of patients aged 65 years; Mean RA disease duration: 12.5 (SD = 9.7) years. Table 1 provides a summary of the rituximab infusions. The incidence of IRRs during or within 24 hours of infusion 1 was 16.2% (95% CI: %) (none serious), consistent with that derived from historical clinical trial data (20.7%). (Figure 1) Infusion 2 was given to 337 patients (96.0%) over 2 hours; 333 completed the infusion and received the full 1,000-mg dose, and four patients did not complete the infusion (three for AEs [none serious], one for another reason). Of these 333 patients, five (1.5%) required an infusion time >2.5 hours. Table 1. Summary of rituximab infusions First infusion rate Day 1 Received infusion 351 Completed 1g 338 Total infusion hours* Mean (SD), range 4.4 (0.3) (4.1, 6.4) Within 4.5 hours 297 (87.9%) >4.5 hours 41 (12.1%) Faster infusion rate Day 15 Day 168 Day 182 Received infusion Infusion at the faster rate Completed 1g (started at faster rate) Total infusion hours Mean (SD), range 2.0 (0.1) (1.8, 3.2) 2.1 (0.3) (1.9, 4.3) 2.0 (0.1) (1.9, 2.4) Within 2.5 hours 328 (98.5%) 276 (95.8%) 277 (100%) >2.5 hours 5 (1.5%) 12 (4.2%) 0 SD = standard deviation *Of those who completed 1g. Of those who completed 1g at the faster rate. 44 New Evidence in Rheumatology March 2014

46 In Supportive Care Oncology The incidence of IRRs for infusion 2 was 6.5% (95% CI: %) (22 patients experienced a total of 30 events), similar to historical data for infusion 2 given at the standard rate (8.1%). (Figure 1) Course 2 data indicated a low incidence of IRRs for infusions 3 and 4. (Figure 1) All IRRs for infusion 2 were Common Terminology Criteria grade 1 or 2, except for two grade 3 events (hypertension and headache), with no grade 4 events. The most commonly observed IRRs for infusion 2 were nausea (1.2%) and chills (0.9%). (Table 2) No serious IRRs or SAEs were reported during or within 24 hours of infusions 1 and 2 (course 1) or infusions 3 and 4 (course 2). (Figure 2) IRRs by prior rituximab experience for all infusions are presented in Figure 3. Table 3 shows the SAEs and infections that occurred during the study. Figure 1. Infusion-related reactions during or within 24 hours of the rituximab infusion 30 Historical Reference* Patients experiencing IRRs (%) Primary endpoint RATE-RA Infusion 1 (Day 1) (n = 351) Infusion 2 (Day 15) (n = 337) Infusion 3 (Day 168) (n = 289) Infusion 4 (Day 182) (n = 278) Labeled rate Faster infusion rate IRRs = infusion-related reactions Error bars are 95% confidence intervals. *Derived from weighted average of incidences reported in historical integrated data of phase II and phase III studies and their open-label extensions as of September 2012 (N = 3,595), based on the proportion of patients with 0, 1, or 2 courses of prior rituximab. Figure 2. Infusion-related reactions during or within 24 hours of the rituximab infusions at faster rates Type of events 6.5% IRRs 0.7% 5.9% 7.1% IRRs + other AEs 1.8% 7.6% CTC grade 3 or 4 AEs Serious IRRs 0.6% 0% 0% 0% 0% 0% Infusion 2 (n = 337) Infusion 3 (n = 289) Infusion 4 (n = 278) Patients with any event (%) AE = adverse event; CI = confidence interval; CTC = Common Terminology Criteria; IRR = infusion-related reaction Error bars are 95% CIs (one-sided for serious IRRs) New Evidence in Rheumatology March

47 Table 2. Infusion-related reactions during or within 24 hours of the second rituximab infusion (faster rate), n = 337 MedDRA preferred term During infusion + within 24 hours post infusion Patients with any IRRs, n (%) 22 (6.5) Nausea 4 (1.2) Chills 3 (0.9) Dizziness 2 (0.6) Headache 2 (0.6) Heart rate increased 2 (0.6) Hypoanesthesia oral 2 (0.6) Pruritus 2 (0.6) Rash 2 (0.6) Abdominal discomfort 1 (0.3) Anxiety 1 (0.3) Erythema 1 (0.3) Flushing 1 (0.3) Hypertension 1 (0.3) Infusion-related reaction 1 (0.3) Migraine 1 (0.3) Pain 1 (0.3) Palpitations 1 (0.3) Pyrexia 1 (0.3) Urticaria 1 (0.3) IRR = infusion-related reaction; MedDRA = Medical Dictionary for Regulatory Activities Note: multiple events in a subject are counted once. Figure 3. Infusion-related reactions by prior rituximab experience Patients (%) Rituximab-naïve Rituximab-experienced Infusion 1 (Day 1) Infusion 2 (Day 15) Infusion 3 (Day 168) Infusion 4 (Day 182) Labeled rate Faster infusion rate 46 New Evidence in Rheumatology March 2014

48 In Supportive Care Oncology Table 3. Serious adverse events and infections during the study All patients (n = 351) Total pt-yrs Serious IRRs SAEs Number of patients (%) 0 (0) Number of patients (%) 30 (8.5) Number of events 33 Rate per 100 pt-yrs (95% CI) 16.0 (11.3, 22.4) Infections* Number of patients (%) 99 (28.2) Number of events 151 Rate per 100 pt-yrs (95% CI) (62.25, 85.64) Serious infections (+ nonserious treated with iv antibiotics)* Number of patients (%) 10 (2.8) Number of events 12 Rate per 100 pt-yrs (95% CI) 5.80 (3.30, 10.22) AEGT = adverse event grouped terms; CI = confidence interval; IRR = infusion-related reaction; iv = intravenous; pt-yrs = patient-years; MedDRA = Medical Dictionary for Regulatory Activities *Including all events that were considered as infections by investigators and/or per MedDRA AEGT list of terms. Key conclusions The incidence of IRRs following infusion 2 (faster rate) was 6.5%, similar to the weighted historical rate of 8.1%. The incidence of IRRs following infusions 3 and 4 (faster rate) was low. The incidence of IRRs following infusion 1 (labeled rate) was 16.2%, similar to the historical rate of 20.7%. No SIRRs occurred during or within 24 hours of any infusions. Overall safety data in this study was consistent with the known rituximab safety profile. Reference: 1. Pritchard CH, Greenwald MW, Kremer JM, et al. Results from the RATE-RA study: a multicenter, single-arm study to evaluate the safety of administering rituximab at a more rapid infusion rate in patients with rheumatoid arthritis. ACR Annual Meeting Abstracts 2013:877. Chatzidionysiou K, et al. ACR 2013:500 Fixed versus on-flare retreatment with rituximab in RA results from the CERERRA collaboration Background Data on how to optimally retreat patients with rheumatoid arthritis (RA) with rituximab have been limited so far. At ACR 2013, Chatzidionysiou and colleagues compared two common retreatment strategies: a fixed retreatment approach (before flare) and retreatment when a flare occurs. 1 Study design Pooled data from the Collaborating European Registries for Rituximab in RA (CERERRA) project were used. RA patients who received at least two retreatments (three courses) with rituximab and for whom information about the strategy for retreatment was available (according to the physician s opinion) were identified. The two retreatment strategies were compared by applying an adjusted mixed model analysis with 28-joint disease activity score (DAS28) improvement as the dependent variable. Key findings A total of 800 patients were retreated at least two times. (Table 1) Retreated because of a flare: n = 616 (442 at first retreatment and 174 at second retreatment). Receiving fixed retreatment: n = 184 (128 at first retreatment and 56 at second retreatment). Baseline characteristics (including age, sex, seropositivity, disease duration, and numbers of prior disease-modifying antirheumatic drugs [DMARDs] and biologics) at first course of rituximab did not differ significantly between the two groups. New Evidence in Rheumatology March

49 Patients retreated on flare had a significantly higher DAS28- erythrocyte sedimentation rate (ESR) at the time of first retreatment (5.1 ± 1.3 vs. 4.1 ± 1.4, p <0.0001), and a higher health assessment questionnaire (HAQ) score (1.5 ± 0.7 vs. 1.3 ± 0.8, p = 0.001), as expected. (Table 1) They had also a higher baseline (at the time of rituximab start) DAS28 (6.3 ± 1.0 vs. 6.1 ± 1.2, p = 0.03). (Table 1) Those retreated on flare were also more likely to be treated with corticosteroids (58% vs. 46%, p = 0.004) but less likely to receive concomitant DMARDs (82% vs. 92%, p = 0.02). (Table 1) In figure 1, the deltadas28 (compared to the DAS28 at the time of rituximab start) for each of the two groups is shown. Patients receiving fixed retreatment had a significantly higher (in absolute number) deltadas28 (p <0.0001) at the start of each cycle, compared to those retreated on flare. In the adjusted mixed model analysis, we compared the two retreatment groups for the first and second retreatment separately using estimated marginal means. For the first retreatment, a fixed retreatment yielded significantly better results than the on-flare retreatment: mean Figure 1. DeltaDAS28-ESR for fixed and on-flare retreatment strategies DeltaDAS28-ESR First retreatment Second retreatment Third retreatment Fixed On-flare DeltaDAS28-ESR = 28-joint disease activity score-erythrocyte sedimentation rate deltadas28 = 2.4 (95% CI: 3.0; 1.7) vs. 1.8 (95% CI: 3.6; 0.03), p < Similar results were found for the second retreatment: mean deltadas28 = 2.6 (95% CI: 3.1; 2.2) vs. 1.6 (95% CI: 1.8; 1.4), p < Table 1. Baseline (start of second or third rituximab cycle) characteristics of patients who were retreated on flare or at fixed intervals First retreatment Second retreatment On-flare N = 442 Fixed N = 128 Difference On-flare N = 174 Fixed N = 56 Difference Months from baseline 10.0 ± 5.7 [442] 8.5 ± 7.1 [128] ± 7.0 [174] 14.4 ± 6.6 [56] < Age (years) 49.5 ± 11.8 [439] 51.1 ± 12.6 [125] ± 12.3 [174] 51.3 ± 10.8 [56] 0.6 Sex (% female) 88 [442] 85 [128] [174] 91 [56] 0.5 Disease Duration (years) 11.0 ± 7.9 [439] 11.0 ± 8.0 [125] ± 8.6 [173] 11.2 ± 8.6 [55] 0.7 RF (% positive) 79 [382] 79 [104] [147] 88 [50] 0.5 Anti-CCP (% positive) 78 [138] 66 [58] [56] 63 [30] 0.07 Number of previous DMARDs 2.4 ± 1.2 [430] 2.5 ± 1.5 [119] ± 1.3 [169] 2.8 ± 1.5 [55] 0.07 Number of previous biologics 0.5 ± 0.7 [432] 0.6 ± 0.7 [118] ± 0.7 [167] 0.7 ± 0.9 [55] 0.7 Baseline DAS ± 1.3 [424] 4.1 ± 1.4 [120] < ± 1.4 [168] 4.0 ± 1.3 [53] < DeltaDAS28 from baseline 0.7 ± 2.0 [164] 2.1 ± 1.4 [53] < DAS28 at rituximab start 6.3 ± 1.0 [414] 6.1 ± 1.2 [122] ± 1.1 [163] 6.3 ± 1.1 [53] 0.7 Baseline HAQ 1.5 ± 0.7 [355] 1.3 ± 0.8 [90] ± 0.7 [141] 1.4 ± 0.7 [26] 0.1 Concomitant DMARDs (%) 82 [442] 92 [128] [174] 54 [56] 1.0 Concomitant corticosteroids (%) 58 [442] 46 [128] [174] 86 [56] 0.4 CCP = cyclic citrullinated peptide; DAS28 = 28-joint disease activity score; DMARD = disease-modifying antirheumatic drug; HAQ = health assessment questionnaire; RF = rheumatoid factor The number of patients with available information is shown in square brackets. 48 New Evidence in Rheumatology March 2014

50 In Supportive Care Oncology Key conclusion A fixed retreatment strategy with rituximab in RA seems to be more effective than the on-flare retreatment strategy. Reference: 1. Chatzidionysiou K, Lie E, Nasonov E, et al. Fixed versus on-flare retreatment with rituximab in RA results from the CERERRA collaboration. ACR Annual Meeting Abstracts 2013:500. Chatzidionysiou K, et al. ACR 2013:496 Effectiveness of repeated courses of rituximab in RA results from the CERERRA collaboration Background Retreatment with rituximab is common clinical practice, although several aspects regarding retreatment, such as frequency, need to be further elucidated. At ACR 2013, Chatzidionysiou and colleagues described the effectiveness of repeated courses of rituximab in a large observational cohort of real-life patients with rheumatoid arthritis (RA). 1 Study design Pooled data from the Collaborating European Registries for Rituximab in RA (CERERRA) project were used. Patients with RA who received at least four cycles with rituximab were identified and included in the analysis. A covariate-adjusted mixed effects model was fitted to the longitudinal 28-joint disease activity score (DAS28) for patients with complete covariate information, including country, sex, age, anti-cyclic citrullinated peptide (CCP) status, number of prior biologics and concomitant disease-modifying antirheumatic drug (DMARD) treatment. Key findings A total of 328 patients met the eligibility criteria for these analyses. At baseline (start of rituximab), the mean (SD) age of patients was 53.5 (12.7) years and the mean (SD) disease duration was 12.2 (8.2) years. (Table 1) Patients were 83% females, 79% rheumatoid factor (RF) positive, and 74% anti-ccp positive. (Table 1) 61% were treated with corticosteroids and 85% with concomitant DMARD. (Table 1) Patients had failed 2.7 (1.5) prior DMARDs and 1.1 (1.0) prior biologic agents. (Table 1) The baseline DAS28 was 6.0 (1.4). (Table 1) Significant heterogeneity between countries was observed in terms of mean time to first retreatment (second cycle), second retreatment (third cycle), and third retreatment (fourth cycle); it seemed to increase with every treatment cycle. Comparison between curves (based on estimated marginal means) revealed significant differences between all curves except between the third and fourth treatment cycles, suggesting that a more stable DAS28 is achieved after second retreatment. (Figure 1) First cycle: 5.6 (95% CI: 5.3, 5.8); Second cycle: 4.7 (95% CI: 4.5, 5.0); Third cycle: 4.5 (95% CI: 4.3, 4.8); and Fourth cycle: 4.4 (95% CI: 4.2, 4.6). Differences between treatment cycles: 1-2: p <0.0001; 1-3: p <0.0001; 1-4: p <0.0001; 2-3: p = 0.05; 2-4: p = 0.003; 3-4: p = New Evidence in Rheumatology March

51 Table 1. Baseline (first cycle of rituximab) characteristics of all patients and of patients who received at least three retreatments with rituximab All patients (N = 3,498) N* At least 4 cycles (N = 328) Age (years) 54.0 ± , ± Sex (% female) , Disease Duration (years) 12.3 ± 9.5 3, ± RF (% positive) , Anti-CCP (% positive) , Number of previous DMARDs 2.5 ± 1.5 2, ± Number of previous biologics 1.0 ± 1.1 3, ± Baseline DAS ± 1.3 2, ± Baseline HAQ 1.6 ± 0.7 2, ± Concomitant DMARDs (%) , Concomitant corticosteroids (%) , CCP = cyclic citrullinated peptide; DAS28 = 28-joint disease activity score; DMARD = disease-modifying antirheumatic drug; HAQ = health assessment questionnaire; RF = rheumatoid factor *The number of patients with available variable information is shown. No significant differences were observed between the two populations. N* Figure 1. Reduction of DAS28-ESR during the first six months after the start of the first through fourth treatment cycles 6 5 Treatment cycle Key conclusions Repeated retreatment with rituximab can lead to further clinical improvement after the first course of rituximab. A trend for stabilization of the disease activity score was observed after the second retreatment. DAS28-ESR Reference: 1. Chatzidionysiou K, Lie E, Nasonov E, et al. Effectiveness of repeated courses of rituximab in RA results from the CERERRA collaboration. ACR Annual Meeting Abstracts 2013: Time (months) DAS28-ESR = 28-joint disease activity score-erythrocyte sedimentation rate 50 New Evidence in Rheumatology March 2014

52 In Supportive Care Oncology Canadian Perspective by Dr. Janet Pope Rituximab is a CD20 antibody that we generally use after one tumour necrosis factor inhibitor (TNF-I) failure in patients with rheumatoid arthritis (RA), particularly in those who are positive for rheumatoid factor and/or anticyclic citrullinated peptide antibodies. In general, I tend to repeat rituximab doses every six months until remission or a low disease state has been achieved, at which point I try to determine a repeat dosing schedule based on time to flare and then select a schedule that is slightly shorter (e.g., one month before an expected flare once that time interval is known). I also follow the usual safety recommendations when giving rituximab (as with any biologic), such as vigilance for serious infections. At the American College of Rheumatology 2013 Annual Meeting, van Vollenhoven et al. presented pooled, long-term safety data from multiple trials over 11 years, which showed that more than a decade of exposure to rituximab did not negatively affect the rates of adverse events (AEs) and serious adverse events (SAEs). This is to be expected, as there are initially more AEs and SAEs with any new immunosuppressive or disease-modifying antirheumatic drug used in RA; however, as adaptation occurs, the rates of AEs and SAEs drop and become stable. In general, infusion-related reactions (IRRs) were found to be mild and manageable, and the vast majority of patients did not withdraw from rituximab use because of them. IRRs often occur in the first dose of any course of infusion, and in this study, the incidence of IRRs did not increase over time. It is reassuring that there were no signals to suggest that repeat dosing of rituximab caused an increase in serious infections, despite observing decreased immunoglobulin levels in some patients. The observed decreases in immunoglobulins were rare, usually transient, and not large enough to be considered clinically relevant. Therefore, there is no reason at this point to consider monitoring the immunoglobulin levels of patients treated with multiple rituximab infusions in clinical practice. Apart from the data on rituximab alone, the study also provided data from a large number of patients to show that subsequent biologics do not affect the safety of rituximab. A higher rate of infections was not observed in patients who received a biologic after receiving rituximab, despite the fact that increased, long-term B-cell depletion was possible. It is comforting to know that if rituximab dosing cannot be repeated for some reason, infection rates should not rise with the use of a new treatment. Also, there appear to be no safety signals for rituximab in terms of the development of malignancies or an increase in cardiac events. This is particularly reassuring for patients with RA who have had previous cancers, as I believe rituximab can be strongly considered for these patients. One limitation of this study is the lack of an untreated control group; however, that is not possible in a study of this length. Additionally, the study selected patients who entered openlabel extensions; these patients typically had a good response and tolerated the drug well. However, this is true of any study utilizing open-label extension data. These results are reassuring, as we now have data from more than a decade of experience and many patient-years of exposure to rituximab; in particular, numerous patients in the early years of repeat dosing. This means that we can tell our patients that the benefit-to-risk ratio of rituximab is very good in both the short-term and long-term. In our clinical practice, we feel reassured that we can continue to retreat our patients who are doing well with rituximab without any new or unexpected safety signals. In general, physicians can feel reassured that rituximab can be prescribed safely and effectively for many years of retreatment. Bessette et al. presented data from the RHUMADATA clinical registry that compared retention rates among various secondline therapies for RA after a first TNF-I failure. The data from this Quebec database show that using rituximab in secondline therapy is superior to a second TNF-I, both in terms of efficacy and durability. This adds Canadian data to multiple international studies showing similar results. 1,2 The patient population in this observational study is similar to the patients we see in our clinic and likely similar to the general population of patients with RA across Canada, with some patients receiving multiple exposures to TNF-Is and some patients treated with a single previous exposure. It is important to keep in mind that this is not a randomized, controlled trial, so the results are confounded by indication and prescribing biases. Additionally, there was no separation of analyses between seropositive and seronegative patients, and there were proportionately more seropositive patients receiving rituximab compared with those receiving a second TNF-I. This is an important factor to consider when interpreting the results, as previous data support the fact that rituximab performs better in seropositive patients than in seronegative patients with RA. 3,4 Among second-line treatments, rituximab is a viable option, as are adalimumab and abatacept. The five-year retention rates among adalimumab, etanercept, infliximab, and rituximab were different in this study, however, it is important to remember that physicians often use their drug of first choice in the first line. A first-line TNF-I is often one the physician has the most positive experience with, and one with which they have observed good retention. New Evidence in Rheumatology March

53 Canadian Perspective by Dr. Janet Pope In my practice, when using second-line biologic therapies after a TNF-I failure, I do not stay in the TNF-I class. An exception to this rule may be if a patient has had an adverse reaction to their current TNF-I but had a very good response, as registry data seem to suggest that there is no difference in outcome when switching to a different class versus changing to another TNF-I. Canadian rheumatologists have prescribed a subsequent TNF-I for years. However, this study by Bessette et al., and others like it, demonstrates that we should strongly consider moving out of the TNF-I class for a second biologic therapy in order to improve outcomes and increase retention. These data may persuade rheumatologists to change their prescribing habits. The study by Pritchard et al. evaluated the rapid infusion mode of delivery for rituximab. Rapid infusions of rituximab have been safely used in patients with lymphoma for many years. The RATE-RA study showed that rapid infusions could also be utilized in patients with RA, with similar safety and risk of overall IRRs compared with those of the traditional infusion rate. The patient population studied here was very similar to the patients we see in our practice. A rapid infusion rate is a positive adjustment to consider for repeat dosing of rituximab, or even for the second infusion of a first course, as this is convenient for patients and saves infusion room time (which saves on nursing costs). Rapid infusion may not be advisable for the first course of rituximab, since IRRs are more common in the first course and especially with the first dose. However, this study observed great safety in administering rituximab over two hours, so perhaps rapid infusions could be an option for all patients. I have prescribed rapid infusions in second and subsequent courses of rituximab, and will now consider using this protocol in the first course as well. In Canada, these data on rapid infusions of rituximab are reassuring, as it saves time for patients, nurses, and infusion room use. Therefore, the rapid infusion protocol is beneficial for everyone involved. References: 1. Finckh A, Ciurea A, Brulhart L, et al. B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents. Arthritis Rheum 2007;56: Emery P, Gottenberg JE, Rubbert-Roth A, et al. Rituximab versus an alternative TNF inihibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study. Ann Rheum Dis 2014; epub ahead of print. doi: /annrheumdis Lal P, Su Z, Holweg CT, et al. Inflammation and autoantibody markers identify rheumatoid arthritis patients with enhanced clinical benefit following rituximab treatment. Arthritis Rheum 2011;63: Mease PJ, Revicki DA, Szechinski J, et al. Improved health-related quality of life for patients with active rheumatoid arthritis receiving rituximab: Results of the Dose-Ranging Assessment: International Clinical Evaluation of Rituximab in Rheumatoid Arthritis (DANCER) Trial. J Rheumatol 2008;35: New Evidence in Rheumatology March 2013

54 Investigator Commentary An Interview with Dr. Katerina Chatzidionysiou on the Use of Rituximab in the Treatment of Rheumatoid Arthritis At the ACR 2013 Annual Meeting, New Evidence spoke with Dr. Katerina Chatzidionysiou about the results of her analyses of rheumatoid arthritis (RA) patients who received rituximab retreatment from 12 European registries in the Collaborating European Registries for Rituximab in RA (CERERRA) collaboration. New Evidence: What is the CERERRA collaboration? Dr. Chatzidionysiou: The CERERRA collaboration is an initiative, started in 2008, between 12 European countries. It is an observational cohort that uses pooled data from national registries on the use of rituximab in RA. The aim of CERERRA is to examine the everyday use of rituximab in patients with RA and to answer questions about rituximab use, including determination of prognostic factors of response, concomitant disease-modifying antirheumatic drug (DMARD) use, optimal dose, and optimal retreatment strategies. New Evidence: What was the rationale for your studies? Dr. Chatzidionysiou: These analyses compared two common retreatment strategies for rituximab: fixed retreatment, where rituximab is administered on a regular schedule, and on-flare, where rituximab is administered when patients experience a flare. New Evidence: What are the advantages and disadvantages of using a fixed interval retreatment protocol? Dr. Chatzidionysiou: The data from our studies suggest that fixed retreatment yields better results compared with on-flare retreatment. We observed that patients retreated on a fixed interval can improve their 28-joint disease activity score (DAS28) upon each retreatment, while this was not observed with an on-flare retreatment schedule. Another advantage is that a set schedule is more structured, both for practicing physicians and for patients. Some disadvantages of fixed retreatment include the economic factor, and the fact that it is sometimes difficult to motivate patients to retreat before a flare if they are feeling well. New Evidence: Which retreatment strategy is used at your institution? Dr. Chatzidionysiou: Our institution does not have an official guideline for retreatment. Approximately 50% of patients receive retreatment on a fixed interval and 50% on-flare, depending on the treating physician. Some countries have guidelines that recommend treating all patients on a fixed interval. New Evidence: What proportion of patients in your study was retreated at fixed intervals? Dr. Chatzidionysiou: We had information about the retreatment strategy for 800 patients, the majority of which were on-flare. Approximately 600 patients were retreated on-flare at least two times, and 184 patients were retreated with a fixed retreatment schedule. New Evidence in Rheumatology March